Next Article in Journal
Synthesis and Evaluation of Neuroprotective Selenoflavanones
Next Article in Special Issue
Local Anesthetic-Induced Neurotoxicity
Previous Article in Journal
Spatiotemporal Expression of p63 in Mouse Epidermal Commitment
Previous Article in Special Issue
Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease
Due to planned maintenance work on our platforms, there might be short service disruptions on Saturday, December 3rd, between 15:00 and 16:00 (CET).
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

Centre of Excellence in Alzheimer’s Disease Research and Care, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup 6027, Australia
School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands 6009, Australia
McCusker Alzheimer’s Research Foundation, Hollywood Medical Centre, 85 Monash Avenue, Suite 22, Nedlands 6009, Australia
Int. J. Mol. Sci. 2015, 16(12), 29554-29573;
Received: 7 October 2015 / Revised: 19 November 2015 / Accepted: 1 December 2015 / Published: 10 December 2015
(This article belongs to the Special Issue Molecular Research in Neurotoxicology)


Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS) on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.

1. Introduction

Interests in lowering peripheral cholesterol levels to reduce the risk of Alzheimer’s disease (AD) have been the focus of many research studies, with particular impact for the regulation of brain amyloid beta (Aβ) metabolism that is closely connected to neurodegenerative disease. Neurodegeneration and brain cholesterol disorders have been the subject of intense research by many laboratories [1,2,3] since the peripheral metabolism of cholesterol is not linked to brain cholesterol metabolism. Cholesterol cannot pass through the blood brain barrier (BBB) with brain cholesterol homeostasis maintained by cholesterol excretion in form of oxysterols. The brain must obtain cholesterol from de novo synthesis with astrocytes, and oligodendrocytes mainly involved in cholesterol synthesis and neurons account for only a small amount of the brain cholesterol [4]. Brain cholesterol homeostasis is maintained by cholesterol excretion in the form of 24S-hydroxysterol (24S OHC), accomplished by the cytochrome P450 species, and in man the brain release approx. 6 mg of 24S OHC into the periphery each day is removed predominantly by the liver [4]. In AD patients studies have shown that cholesterol metabolism is disturbed with elevated 24S OHC levels possibly related to neuronal death and neurodegeneration [4]. An integrated approach to advance our knowledge require the identification of toxic dietary components such as bacterial lipopolysaccharides (LPS) and fungal mycotoxins that have become of importance to neuron apoptosis in neurodegenerative disease, versus the brain cholesterol dyshomeostasis that is linked to Aβ oligomerization, that determines neuron survival for the treatment of neurodegeneration and AD.
The interests in hypercholesterolerolemia with low high density lipoproteins (HDL) and high low density lipoproteins (LDL) in the plasma of AD patients [4] has increased with relevance to diet, nutrition and assessment of insulin resistance (obesity, diabetes)/atherosclerosis with elevated phospholipid transfer activity (PLTP) [5,6,7] associated with neurodegeneration and AD. Diets that are healthy stabilize insulin resistance, increase HDL, and promote neuron and synapse maintenance in the brain [1,4]. The consumption of mycotoxins by mycotoxin contamination in food [8,9,10,11,12,13,14,15,16] has adverse human health [17] effects and now has become of global interest. Mycotoxin contamination has been found in cereal/grains, coffee (ochratoxin A), apples, apple juice, nuts, and nut products [8,9,10,11,12,13,14,15,16,17]. Mycotoxins are the toxic secondary metabolites of molds and fungi and many of which are pathogenic to humans. Mycotoxins enter the body through the skin, digestive tract, or through respiration and when the body with aging accumulates a few milligrams [8,9,10,11,12,13,14,15,16,17] the lethal effects of mycotoxins have been associated with various organs.
Diets high in cholesterol (Figure 1) may promote rapid absorption of various mycotoxins with increased membrane cholesterol that sequester mycotoxins [18]. Sequestration of mycotoxins by a cholesterol model system has now become an important technology to prevent mycotoxin toxicity [18]. Furthermore, mycotoxin levels are associated with hypercholesterolemia and have detrimental effects on liver cholesterol metabolism by effects on cholesterol synthesis [19]. Mycotoxins have been shown to bind to lipoproteins in human and animal plasma and induce hypercholesterolemia [20]. The effects of ingestion of a cholesterol diet involve intestinal transport of cholesterol in lipoproteins such as chylomicrons and chylomicron remnants with delivery of cholesterol to the liver [21,22]. The liver synthesizes very low density lipoprotein (VLDL) and transports cholesterol to peripheral tissues [23].
Figure 1. Links between diet and neurodegeneration has escalated with the involvement of bacterial lipopolysaccarides and fungal mycotoxins in amyloid beta (Aβ) homeostasis. Nutrition and food science with diets that promote the low absorption of lipophilic LPS and mycotoxin into lipoproteins with the rapid hepatic metabolism of LPS/mycotoxins to the liver, have become important to prevent early neurotoxicity and to promote the survival of neurons with age.
Figure 1. Links between diet and neurodegeneration has escalated with the involvement of bacterial lipopolysaccarides and fungal mycotoxins in amyloid beta (Aβ) homeostasis. Nutrition and food science with diets that promote the low absorption of lipophilic LPS and mycotoxin into lipoproteins with the rapid hepatic metabolism of LPS/mycotoxins to the liver, have become important to prevent early neurotoxicity and to promote the survival of neurons with age.
Ijms 16 26190 g001
These lipoproteins have generally spherical structures consisting of a neutral lipid core of cholesteryl esters and triglycerides and a surface layer of phospholipids, unesterified cholesterol and various apolipoproteins such as apolipoproten E and apoliprotein AI [24]. Mycotoxins are lipophilic [25] and after ingestion of fat and cholesterol can be incorporated into lipoproteins (Figure 1) with sequestration by cholesterol in the surface of lipoprotein particles. Interests in lipoprotein sequestration may allow reduction in mycotoxin toxicity [19]. The effects of delivery of mycotoxins to the liver [25] interfere with the VLDL and HDL cholesterol metabolism and are responsible with hypercholesterolemia and atherosclerosis [19]. In various studies in animals the role of mycotoxins in neurological disease [26,27,28,29,30] have indicated effects on oxidative stress pathways involved in neurotoxicity [31]. Mycotoxins such as macrocyclic trichothecenes [32,33,34] and ochratoxin A (OTA) have been shown to induce apoptosis of neuronal cells [35,36,37] and contribute to the pathogenesis of neurodegenerative diseases such as AD and PD. Other cells such as hepatocytes, platelets (cholesterol levels), macrophages, endothelial cells, and astrocytes are susceptible to mycotoxin toxicity. Mycotoxins have an acute or chronic effect in man and depend on the nature of mycotoxin and the composition of the diet that are associated with the development of diseases of the liver (cancer), kidney, lungs, reproductive system, and gastrointestinal tract that may also involve the immune system and hormone imbalances. Interests in the effects of mycotoxin and its transport to the brain have accelerated with the current global NAFLD epidemic with corruption of mycotoxin clearance by the liver with relevance to accelerated neurodegeneration and amyloidosis.
The effects of bacterial lipopolysaccharides (LPS) on dyslipidemia indicate that the abnormal clearance and metabolism of fungal mycotoxins in lipoproteins are linked to hypercholesterolemia and neurodegeneration (Figure 1). The synergistic effect of LPS and mycotoxins interfere by post transcriptional and post translational modifications to cells and disturb cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/Aβ interactions relevant to hypercholesterolemia with close connections to Alzheimer’s disease. Hypercholesterolemia is one of the major causes of NAFLD and blood brain barrier disease (BBB) and with aging the plasma oxysterol levels increase in chronic diseases [38,39,40,41,42,43] that accelerate the transport of HDL to the brain [44]. HDL is closely linked to oxysterol induced cell damage and as oxysterol contents increase in HDL the prevention of oxysterol damage to peripheral cells and neurons occurs. In AD brain oxysterol levels are increased and disturb the BBB associated with increased Aβ production [45,46]. Hypercholesterolemia and NAFLD induce BBB disease with increased LPS and mycotoxin transport to the brain with neurodegeneration. Individuals with insulin resistance such as obese and diabetic individuals have BBB disease [47] and transport of LPS and mycotoxin corrupt BBB disease important to drug therapy associated with accelerated brain aging. The cholesterol lowering drug Simvastation has been shown to block disturbed BBB disease induced by hypercholesterolemia [48].
In AD BBB disease has been reported and its early detection has become important to the prevention of neurodegeneration [49,50]. The BBB microvasculature is composed of a capillary basement membrane containing endothelial cells, astrocyte end feet, and pericytes inside the basement membrane. Transport of mycotoxins that are non-polar cross the BBB rapidly in vivo [51,52] or may involve LPS induced BBB permeability [53,54] to mycotoxin transport across BBB membranes. Myoctoxins such as T-2 or HT-2 toxin cause BBB disruption by the influence on the tight junction in the BBB [55]. Mycotoxins may corrupt BBB membranes by their incorporation into the membranes that induce membrane changes and lipid peroxidation [31]. LPS induced BBB permeability has been shown and involves increased reactive BBB opening with the transport of proteins across the BBB such as insulin [54] and with the impairment of the BBB transport of Aβ from the brain [56,57] with corruption of the peripheral Aβ clearance pathway. Hypercholesterolemia induced BBB permeability that involve oxysterols are also linked to LPS and mycotoxin induction of BBB disease in NAFLD and neurodegeneration.
Diets that contain alcohol, fat, and carbohydrate stimulate the absorption of LPS [58,59,60,61] that can rapidly insert into cell membranes, with a preference for insertion and partition into cholesterol/sphingomyelin domains in lipoproteins and cell membranes [62,63] with relevance to mycotoxin transport. LPS has been shown to effect cholesterol efflux, with effects on hepatic lipoprotein metabolism and dyslipidemia [64,65,66,67,68]. LPS administration in mice are closely linked with connections to insulin resistance with effects on NAFLD, systemic inflammation and the metabolic syndrome. The importance of LPS on the regulation of cholesterol and Aβ homeostasis [69,70,71] involve apolipoprotein E (apo E-PLTP) that are closely linked to NAFLD [64,65,66,67,68] and involve the metabolism of liver mycotoxins [25,26]. The synergism of LPS and mycotoxin on NAFLD involve the corruption of peripheral Aβ metabolism [69,70,71], associated with increased plasma cholesterol, oxysterol, mycotoxin levels, and low HDL levels involved with early neurotoxicity in various neurodegenerative diseases.

2. Mycotoxin and LPS Regulate Cholesterol and Aβ Metabolism

The role of cholesterol in modulating the expression of amyloid precursor protein (APP) and the levels of cell Aβ have been reported [4,7] and Aβ metabolism connected to the low density lipoprotein receptor (LDLr) family [4]. Cholesterol modulates Aβ levels and Aβ acts on lipid metabolism by effects on cholesterol synthesis that may play an important role in sphingomyelin/ceramide metabolism [4]. In the brain and liver, the LDLr family play an important role in the metabolism of cholesterol and Aβ with the LDL receptor related protein 1 (LRP1) closely linked to AD [72,73,74]. LRP1 and LDLr acts on the blood brain barrier (BBB), and regulate the transport of Aβ to the periphery from the brain [72,73,74]. The corruption of LPS of peripheral and brain Aβ transport [69,70,71] involve disturbed membrane cholesterol homeostasis with membrane cholesterol involved in mycotoxin sequestration [19,25].
Cholesterol is an essential membrane component that influences hepatocyte and neuron function and in neurons, cholesterol is critical for the maintenance of synaptic connections. Membrane lipids such as cholesterol play an important role with cholesterol related proteins in neurons that conduct electrical impulses in association with membrane proteins. In membranes the association of phospholipids, glycosphingolipids such as ceramide or gangliosides, and glycerophospholipids (plasmalogen) with cholesterol have marked effects on membrane protein structure and function with the regulation of ion pumps [4,7]. Mycotoxins such as patulin in cultured cells have been shown to interfere with membrane function and ion channels involved in the transduction of extracellular an intracellular signals [25,75]. Interactions with membrane cholesterol involve mycotoxin sequestration and LPS that bind to the cholesterol/sphingomyelin domains in membranes [62,63].
LPS are endotoxins and essential components of the outer membrane of all Gram-negative bacteria. Bacterial LPSs are dimeric molecules consisting of a polysaccharide moiety linked to a lipid core termed Lipid A which is anchored within the cell membrane. Lipid rafts/caveolae containing sphingomyelin and cholesterol form microdomains in cell membranes for the recruitment of lipid modified proteins such as Aβ oligomers. LPS may influence membrane cholesterol by binding to cell membranes and lipoproteins and its packing in the membrane allows the increased interaction or displacement of the Aβ peptide, that leads to electrostatic Aβ oligomer formation and fibril formation [69].
LPS disturbance in cell cholesterol efflux involve the liver X receptor and ATP-binding cassette transporter proteins (LXR-ABCA1) interactions [76]. Furthermore, LPS interference with cholesterol interacting proteins such as caveolin-1, which is a major component of caveolae (membrane microdomains, 50–100 nm), involve corruption of cellular cholesterol endocytosis [77,78,79,80,81,82,83,84,85,86,87,88]. LPS has been shown to effect caveolin expression [89,90], apo AI [91,92,93] and apo E [69] with effects on neutralization of cholesterol efflux that involve ABCA1 [94,95,96]. The effects of LPS on plasma cholesterol metabolism involve HDL metabolism with neutralization of apo AI [91,92,93] associated with low HDL levels. Increased membrane cholesterol levels induced by LPS delay hepatic mycotoxin metabolism in membranes. Increased cholesterol levels in membranes have been associated with increased Aβ oligomers with toxic effects on membrane lipid peroxidation [69,70,71,97] that may involve cholesterol interacting proteins such as the GPCRs [98,99,100,101,102,103]. LPS effects on caveolin-1 expression involve ABCA1 and insulin receptor levels with effects on Aβ production and relevance to AD [104,105,106,107,108,109,110,111].

3. LPS/Mycotoxin Interactions Interfere with Apolipoprotein E/Aβ Peptide Interactions and Determine Neuron Survival

Novel information on dietary components that perturb the interactions between two key peptides (apo E and Aβ) has the potential to considerably improve brain (neuron) and liver Aβ metabolism with relevance to insulin resistance and neurodegeneration [112]. The understanding of specific toxins such as bacterial LPS and mycotoxins that interfere with the transport of apo E mediating Aβ clearance in the brain and liver is clearly needed. The integrated approach will advance our knowledge of the importance of diet [4] in this transport process relevant to cholesterol/Aβ homeostasis, that provide insights in relation to the toxic process that leads to neurodegeneration and AD.
Apo E is an important apolipoprotein in lipid metabolism with multiple roles in cell biology [112]. Interactions of apo E isoforms with the Aβ peptide have been studied in various laboratories [112] to understand how apo E4 promotes risk for neurodegeneration. The hypothesis that the interaction between these peptides is determined by the nature of associated lipids such as cholesterol which alters their conformation and determines the cellular uptake of the apo E/Aβ complex is important to the field of AD. The role of the apo E (E2, E3, E4) isoforms and their specific interactions with the Aβ peptide have been reported and integrates cholesterol metabolism with AD [112].
The kinetics of binding between apo E and Aβ are determined by different isoforms of apo E and LPS has now been shown to neutralize apo E-PLTP activity [69,70,71] with the corruption of the apo E-Aβ interaction [69,70,71,112]. Apo E4 and its association with protein misfolding of Aβ has been studied extensively and cell membrane LPS and mycotoxin contents have become important to apo E3 individuals with relevance to susceptibility to Aβ oligomer formation and neurodegeneration (Figure 2). Membrane-bound and soluble proteins have been shown to bind LPS such as LPS binding protein (lipoproteins), toll-like receptor (TLR), GPCR, and CD14 receptor. In the central nervous system, systemic LPS injection initiates the acute phase response and upregulates membrane CD14 receptor that controls TLR4 endocytosis [59,113] and induces microglial activation that results in neurodegeneration and Parkinson’s disease (PD) [114]. The CD14 receptor is referred to as the LPS receptor and is involved in the phagocytosis of the Aβ peptide [115,116,117,118]. Mycotoxins have also been shown to be involved in CD14 receptor expression in macrophages [119]. LPS induction of APPs [69,70] are linked to the CD14 receptor with the levels linked to liver inflammation and NAFLD. LPS and the mycotoxin patulin have been shown to effect hepatic genomic stability [69] with effects on reverse cholesterol transport in macrophages and with macrophage activation that involve LPS and mycotoxin [59,113,119].
LPS in brain cells improves the scientific understanding of membrane cholesterol and Aβ oligomer formation in the brain. Astrocytes have been shown to accumulate neuronal Aβ to prevent Aβ plaque development [120,121,122,123]. In the brain the HDL are the major lipoproteins involved in the turnover of brain cholesterol [124]. The astrocyte synthesizes apo E-PLTP with apo E-PLTP that play an important role in cholesterol and Aβ metabolism [125,126,127,128] that determine neuron synapse formation. The disturbances in brain HDL (apo AI) lipoprotein metabolism induced by LPS [91,92,93] also effect astrocyte apo E [69] and the LDLr [129] with increased brain cholesterol linked to poor neuron survival with connections to electrostatic Aβ oligomer formation [130]. Furthermore, LPS corruption of the apo E and hepatic Aβ metabolism are associated with disturbed brain cholesterol levels relevant to disturbed apo E-PLTP activity involved in the regulation of Aβ [130]. Furthermore, LPS regulated cholesterol sequestration of mycotoxins in cell membranes displace Aβ peptides with abnormal effects of mycotoxin such as patulin on various biological functions that regulate membrane fluidity and ion channel function in cells from various tissues [25,131,132,133,134,135].
LPS and mycotoxins regulate acute phase proteins such as serum amyloid protein A [69,112,136] and C reactive protein [137,138] involved in amyloidosis in AD. LPS has been shown to reduce the release of albumin from the liver in man with relevance to the principal role of albumin in peripheral and brain Aβ aggregation [70]. In rats, patulin had marked effects on liver albumin and the plasma protein fraction that was found to be markedly decreased was albumin [139]. Therefore the peripheral effects of LPS and patulin nullify the albumin mediated Aβ and apo E mediated transport from the brain [70].
Figure 2. Bacterial LPS and mycotoxin promote dyslipidemia, electrostatic Aβ oligomer formation via post translational or post transcriptional modifications. (1) Bacterial LPS and mycotoxin induce dyslipidemia and NAFLD; (2) LPS and mycotoxin alter cell and membrane cholesterol homeostasis with increased Aβ formation; (3) Defective Sirtuin 1 (Sirt 1) post transcriptional regulation and post-translational modifications of cholesterol interacting proteins by LPS/mycotoxin neutralize apo E and increase Aβ oligomerization with connections to insulin resistance and AD; (4) Electrostatic Aβ oligomer formation may be independent of the early neuron apoptosis associated with neurotoxicity in individuals with insulin resistance and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease).
Figure 2. Bacterial LPS and mycotoxin promote dyslipidemia, electrostatic Aβ oligomer formation via post translational or post transcriptional modifications. (1) Bacterial LPS and mycotoxin induce dyslipidemia and NAFLD; (2) LPS and mycotoxin alter cell and membrane cholesterol homeostasis with increased Aβ formation; (3) Defective Sirtuin 1 (Sirt 1) post transcriptional regulation and post-translational modifications of cholesterol interacting proteins by LPS/mycotoxin neutralize apo E and increase Aβ oligomerization with connections to insulin resistance and AD; (4) Electrostatic Aβ oligomer formation may be independent of the early neuron apoptosis associated with neurotoxicity in individuals with insulin resistance and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease).
Ijms 16 26190 g002

4. Patulin and LPS Effect Electrostatic Aβ Oligomer Formation via Post Translational or Post Transcriptional Modifications

Specific amino acids such as cysteine are involved in post-translational modifications that include oxidation, nitrosylation, or disulfide bond formation [140,141] with electrostatics that have and play important roles in biology such as toxic Aβ oligomer formation. Cysteine residues are important to many protein functions and patulin has been shown to induce cysteine intra and inter molecular crosslinks that effect many cholesterol interacting proteins such as GPCR receptor activation, apo AI-ABCA1 cholesterol dependent efflux, LRP-1 associated LPS/mycotoxin metabolism, LDLr binding of lipoproteins, apo E (E2, E3, E4)/Aβ interactions, and phospholipid transport protein synthesis/secretion that effects apo E-PLTP activity [138,142,143,144,145,146,147,148,149,150,151,152]. The mycotoxin patulin has been shown to be neurotoxic and in mice patulin has been shown to induce brain damage [153,154]. Patulin has been shown to induce intra- and intermolecular protein crosslinks in vitro of other amino acids such as lysine, histidine side chains, and alpha-amino groups [155]. These three amino acids (cysteine, lysine, histidine) are found in Aβ [156,157,158,159,160] with effects of patulin on these amino acids that possibly are responsible for Aβ electrostatic nature and promotion of Aβ oligomer formation.
Interest in dietary regulation of liver LPS and mycotoxin metabolism involves Sirtuin 1 (Sirt1). Sirt 1 is one of the nuclear receptors known to regulate several cell functions by deacetylating both histone and non-histone targets [161,162]. Sirt 1 is a NAD(+)dependent class III histone deacetylase protein that targets transcription factors to adapt gene expression to metabolic activity, insulin resistance and inflammation in chronic diseases [163,164]. Nutritional regulation (calorie restriction and high fat feeding) of Sirt1 is involved in neuron proliferation with effects on cellular cholesterol closely linked to Aβ clearance in AD [165,166,167]. In mammalian cells, patulin has been shown to have toxic effects in the nucleus [153,154] with posttranslational modification of cysteine residues by patulin relevant to the nutrient sensing nuclear receptor Sirt 1 that contains a zinc centre (activator) co-ordinated by four cysteine residues that are critical for its function [168]. Many mycotoxins such as patulin interfere with DNA repair in liver cells [169] and override Sirt 1’s involvement in DNA repair and telomere maintenance in cells [170]. Patulin and its toxic effects on cysteine cross links in Sirt 1 dysfunction may be relevant to the corruption of nitric oxide and neural pathways [171]. LPS and mycotoxins are involved with disturbed cellular nitric oxide homeostasis with relevance to nitric oxide dyshomeostasis and Aβ metabolism [171]. Nitric oxide neurotoxicity [171,172] induced by LPS and mycotoxins may generate the strong oxidant peroxynitrite [173,174] involved in the inhibition of Sirt 1 binding to zinc [168,175].
Sirt 1 is involved in the regulation of nuclear liver X receptors linked to ABCA1 (cholesterol metabolism) targets in the liver and brain [4]. The interest in neuron glucose metabolism has accelerated with the role of Sirt 1 and its role in transcriptional regulation of p53 [176,177] linked to p53 transcriptional regulation of caveolin 1 expression [178,179,180] associated with insulin receptor transport and activity [105,106,107,108]. LPS has been shown to repress Sirt 1 [177,181] and caveolin expression [89,90] with implications to class B, type I scavenger receptor [67] involved in cholesterol trafficking and HDL levels. Sirt 1 downregulation in the liver and brain prevents mycotoxin metabolism with effects on NAFLD and neurodegeneration. Injections with l-cysteine prevented the effect of LPS in liver injury [182] with apo AI and HDL linked to LPS neutralization [91,92,93].
Synergism of LPS and mycotoxin interactions in cells involving accelerated inflammation and patulin levels should be monitored to prevent complete neuron apoptosis and brain Aβ oligomerization with implications to shifts in protein homeostasis (Figure 2). The effects of LPS on inflammation in the BBB have been reported to involve caveolin-1 and α-synuclein [183,184,185,186]. LPS and relevance to Aβ/α-synuclein transport and insulin resistance has escalated [71] with relevance to BBB permeability and corruption of the neuronal Aβ transport across the BBB to the periphery for metabolism by the liver. The effects of LPS on the release of acute phase proteins [69,70,112] involve interactions with Aβ and α-synuclein oligomers to delay or promote Aβ oligomerization.
LPS and α-synuclein involve corruption of membrane cholesterol flux to HDL and mycotoxin transport from peripheral cells/neurons by binding of α-synuclein to membrane cholesterol (isooctyl chain) to prevent cholesterol metabolism [187]. The LPS repression of Sirt 1 [181] promotes defective cholesterol efflux in the periphery and brain with increased levels of alpha synuclein and Aβ (Figure 2). α-synuclein effects on increased BBB permeability induced by LPS/α-synuclein interactions [69,70,71] promote the transport of mycotoxins into the brain and in the absence of LPS the BBB transport of mycotoxins may not be relevant. In the aging process, the increased concentrations of LPS are transported to the brain (LPS mediated) and its neurotoxic effect on apelin-Sirt 1 interactions induce alterations in NO homeostasis [167] and determine neuron survival [188]. Furthermore, patulin [155] may have direct toxic effects on the inhibition of the apo E and Aβ cysteine interaction in membranes and determine Aβ oligomer formation and NO toxicity [189,190] in the brain with early aging and AD. Furthermore, electrostatic Aβ oligomer formation may involve α-synuclein (cysteine, histidine) by the effects of patulin on intra and intermolecular protein crosslinks involving cysteine, lysine, and histidine side chains [155] involved in protein oligomerization [71,191,192]. Patulin effects on lipid-protein interactions may also involve disturbed crosslinks that involve Aβ histidine 13 binding to ganglioside [193] associated with Aβ aggregation.

5. Nutritional Diets Reduce Neurotoxins and Allow Effective Drug Treatment Programs

LPS dysregulation of nuclear Sirt 1 [177,181] has become important with relevance to hepatic cholesterol metabolism [76,77,78] that are now closely connected to cellular mycotoxin (ng–µg) and Aβ metabolism [71]. As aging occurs Sirt 1 is dysregulated [194,195,196] in the developing world with Sirt 1 downregulation now associated with various chronic diseases. Diets that are healthy do not contain LPS [197,198] or mycotoxin [10,11,15,25] with both components involved with disturbed cell cholesterol homeostasis/Aβ metabolism and absence of these components from the human plasma allow effective drug therapy such as statin drug treatment that may maintain proper synaptic function and neuron survival. Statins, patulin, and Aβ have been shown to inhibit protein prenylation [199,200,201] with effects on cell cholesterol sequestration and Aβ oligomer formation.
Food patulin levels should be reduced with relevance to the toxic effects of patulin [202] in peripheral tissues. Patulin levels [203] have been measured and daily intake can be high and found in foods such as fresh and dried fruits, processing stages of bread, apple (apple juice concentrates 50 µg/kg), and cereals. Patulin levels in apple juice concentrates, blue cheese, and cereals have been clearly documented. Bacterial lipopolysaccharides are also found in unpasteurized fruit juices, ciders, bread (oven baked poorly), and fruits (diverse bacterial populations) [197,198] and toxic effects of patulin may involve LPS interactions. Strict surveillance of apple ripening and cheese making/ripening has to be implemented to ensure patulin levels are low with increased levels associated with the aging process.
Consumption of apples and cheese are a rich source of pyruvic acid (amino acid metabolism) and leucine and ingestion of these nutrients has been associated with activation of Sirt 1 [195]. The potent effects of apple and cheese spoilage that produces patulin is concentrated in the liver with the induction of NAFLD in the developing world. The OTA that is found in the rind and inner part of the cheese and in alcohol (beer, wine) rise in the blood plasma with NAFLD linked to increased OTA transport to the brain. Alcohol (apple cocktail, beer, wine) promotes the intestinal absorption of LPS/patulin/OTA and alcohol is a Sirt 1 inhibitor [170]. Alcohol contains patulin/OTA [204] with relevance to the hepatic metabolism of mycotoxin and Aβ.
The failure of the anti-obese drug program in Western countries [205] with central acting CNS drugs may be better understood with high fibre diets that activate Sirt 1 in the liver with the maintenance of hepatic fatty, cholesterol, glucose metabolism that is closely connected to hepatic LPS/mycotoxin metabolism. The antipsychotic/antidepressants used to treat neurodegeneration interact with cell membranes [181] and the role of patulin and LPS interactions (nitric oxide toxicity) may be involved with ineffective drug therapy in the brain. High fibre diets that contain both fruits and vegetables (phystosterols) improve Aβ metabolism [4] but mycotoxin/LPS contamination [10,11,15,25,197,198] disrupt membrane phytosterol therapy with LPS/mycotoxin contamination associated with the packing, storage, transportation, handling, and processing of fresh produce to the final destination. Phytosterol consumption regulates hepatic cholesterol metabolism with the liver involved with rapid detoxification (hepatic biotranformation enzymes, cytochrome p450) of mycotoxins by elimination into bile in animals and man [206].
In developing countries, the increase in xenobiotics [207] in polluted environments such as drugs, drug metabolites, synthetic pesticides, and herbicides may delay mycotoxin metabolism with mycotoxin related neurotoxicity. Diets that activate the Sirt 1/pregnane X receptor pathway respond by the expression of cytochrome p450 that may allow rapid metabolism of xenobiotics (food, air, water) and mycotoxins (food, air, water) [207] with reduced neurotoxin transport to the brain. The xenobiotics consumed may corrupt the hepatic elimination of mycotoxins (vice versa) with the induction of NAFLD that is now closely linked to neurodegeneration.
Interests in increased hepatic cholesterol metabolism and transport to the bile has increased with phosphatidylinositol (PI) doses [208] essential for lowering liver cholesterol with increased plasma apo AI (HDL levels). The cell membrane carries a net negative surface charge with the presence of anionic lipids, which constitute 10% of the total lipids in the plasma membrane [112]. PIs in cell membranes consist of 1% of the lipids that are physiopathological modulators of membrane cholesterol and amyloid homeostasis [112]. LPS and patulin effects on cell membranes corrupt PI and Aβ membrane interactions [112]. The addition of PI (2–5 gm/meal) accelerated liver cholesterol metabolism over a two-week period [208] with relevance of PI ingestion to improve hepatic LPS/mycotoxin metabolism. Mycotoxins/LPS are closely connected with platelet function and appropriate PI consumption is required to assist with platelet cholesterol levels, Aβ production, and prevention of platelet aggregation [32,33,209,210,211,212]. The importance of consumption of nuts as a rich source of PI has accelerated with relevance to doses of PI ingestion that override caveolin-1 downregulation (Sirt 1) that is a phosphatidylinositol 3-kinase sensitive [213] with the prevention of hypercholesterolemia, NAFLD, and amyloidosis [7,176,177,194,195,196]. However, nut consumption should be carefully monitored with relevance to NO composition and mycotoxin content [15].

6. Conclusions

Food and nutrition guidelines for the handling and processing of fresh fruit, bread, and vegetables are essential and fresh produce may require cold preservation procedures to prevent minimal bacterial and fungi contamination of food. In the developing world, the food content of LPS/mycotoxin levels determine nuclear receptor defects such as Sirt 1 downregulation involved in the survival of neurons. Small amounts of LPS/mycotoxin in food/alcohol that are absorbed into the plasma, are rapidly cleared by the liver when liver Sirt 1 is under circadian regulation. The diabetes epidemic (Sirt 1 senescence) in the developing world may related to the appetite dysregulation, with absorption of higher contents of LPS/mycotoxins that induce early insulin resistance and cholesterol efflux disturbances associated with NAFLD and neuron dysfunction relevant to various chronic diseases. Diets that are Western style (high calorie, cholesterol) may promote increased absorption of xenobiotics that induce NAFLD and neurodegeneration. Drugs and xenobiotics consumed (drug regime) by various obese and diabetic individuals should be assessed since common pathways shared with xenobiotics/LPS/mycotoxins may not allow hepatic metabolism of LPS/mycotoxins (dyslipidemia) with increased delivery of ochratoxin A (coffee), patulin (apple), and LPS (cheese, fruit, vegetables) to the brain, associated with early neurodegeneration and independent of the structural conversion to electrostatic Aβ oligomer formation.


This work was supported by grants from Edith Cowan University, the McCusker Alzheimer’s Research Foundation, and the National Health and Medical Research Council.

Conflicts of Interest

The author declares no conflict of interest.


  1. Martín, M.G.; Pfrieger, F.; Dotti, C.G. Cholesterol in brain disease: Sometimes determinant and frequently implicated. EMBO Rep. 2014, 15, 1036–1052. [Google Scholar] [CrossRef] [PubMed]
  2. Vance, J.E. Dysregulation of cholesterol balance in the brain: Contribution to neurodegenerative diseases. Dis. Models Mech. 2012, 5, 746–755. [Google Scholar] [CrossRef] [PubMed]
  3. Benarroch, E.E. Brain cholesterol metabolism and neurologic disease. Neurology 2008, 71, 1368–1373. [Google Scholar] [CrossRef] [PubMed]
  4. Martins, I.J.; Fernando, W. High fibre diets and Alzheimer’s disease. Food Nutr. Sci. 2014, 5, 410–424. [Google Scholar] [CrossRef]
  5. Jonkers, I.J.; Smelt, A.H.; Hattori, H.; Scheek, L.M.; van Gent, T.; de Man, F.H.; van der Laarse, A.; van Tol, A. Decreased PLTP mass but elevated PLTP activity linked to insulin resistance in HTG: Effects of bezafibrate therapy. J. Lipid Res. 2003, 44, 1462–1469. [Google Scholar] [CrossRef] [PubMed]
  6. Tan, K.C.; Shiu, S.W.; Wong, Y.; Wong, W.K.; Tam, S. Plasma apolipoprotein E concentration is an important determinant of phospholipid transfer protein activity in type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 2006, 22, 307–312. [Google Scholar] [CrossRef] [PubMed]
  7. Martins, I.J.; Creegan, R. Links between insulin resistance, lipoprotein metabolism and amyloidosis in Alzheimer’s disease. Health 2014, 6, 1549–1579. [Google Scholar] [CrossRef]
  8. Dombrink-Kurtzman, M.A. Chapter 2—Economic Aspects of Mycotoxins in Fruits and Vegetables. In Mycotoxins in Fruits and Vegetables; Academic Press: San Diego, CA, USA, 2008; pp. 27–44. [Google Scholar]
  9. Hymery, N.; Vasseur, V.; Coton, M.; Mounier, J.; Jany, J.L.; Barbier, G.; Coton, E. Filamentous fungi and mycotoxins in cheese: A review. Compr. Rev. Food Sci. Food Saf. 2014, 13, 437–456. [Google Scholar] [CrossRef]
  10. Makun, H.S. (Ed.) Mycotoxin and Food Safety in Developing Countries. 2013. Available online: (accessed on 9 September 2015).
  11. Shephard, G.S. Impact of mycotoxins on human health in developing countries. Food Addit. Contam. 2008, 25, 146–151. [Google Scholar] [CrossRef] [PubMed]
  12. Miller, J.D. Fungi and mycotoxins in grain: Implications for stored product research. J. Stored Prod. Res. 1995, 31, 1–16. [Google Scholar] [CrossRef]
  13. Levi, C. Mycotoxins in coffee. J. Assoc. Off. Anal. Chem. 1980, 63, 1282–1285. [Google Scholar] [PubMed]
  14. Wild, C.P.; Gong, Y.Y. Mycotoxins and human disease: A largely ignored global health issue. Carcinogenesis 2010, 31, 71–82. [Google Scholar] [CrossRef] [PubMed]
  15. Afsah-Hejri, L.; Jinap, S.; Hajeb, P.; Radu, S. A review on mycotoxins in food and feed: Malaysia case study. Shakibazadeh 2013, 12, 629–651. [Google Scholar]
  16. Culliao, A.G.; Barcelo, J.M. Fungal and mycotoxin contamination of coffee beans in Benguet province, Philippines. Food Addit. Contam. 2015, 32, 250–260. [Google Scholar] [CrossRef] [PubMed]
  17. Peraica, M.; Radić, B.; Lucić, A.; Pavlović, M. Toxic effects of mycotoxins in humans. Bull. World Health Organ 1999, 77, 754–766. [Google Scholar] [PubMed]
  18. Modified Nanoparticles for Lipophilic Toxin Sequestration Published on Modified Nanoparticles for Lipophilic Toxin Sequestration Principal Investigator: Weston Daniel Research Scientist, 2013. Northwestern University. Available online: (accessed on 7 May 2015).
  19. Anyanwu, E.; Ehiri, J.; Kanu, I. High cholesterol levels and chronic exposure to toxigenic molds in damp buildings: A high risk for cardiovascular diseases and stroke. Internet J. Toxicol. 2006, 3, 1–9. [Google Scholar]
  20. Costantini, A.V.; Am Muehlbach, M.D. (Eds.) Mycotoxin-induced atherosclerosis. The Fungalbionic Book Series. Available online: (accessed on 4 September 2015).
  21. Martins, I.J.; Mortimer, B.-C.; Redgrave, T.G. Effect of the ACAT inhibitor CL 277,082 on apolipoprotein B48 transport in mesenteric lymph and on the plasma clearance of chylomicrons and remnants. Arteriosclerosis. Thromb. Vasc. Biol. 1997, 17, 211–216. [Google Scholar] [CrossRef]
  22. Martins, I.J.; Sainsbury, A.J.; Mamo, J.C.L.; Redgrave, T.G. Lipid and apolipoprotein B48 transport in mesenteric lymph and the effect of hyperphagia on chylomicron clearance in insulin-deficient rats. Diabetologia 1994, 37, 238–246. [Google Scholar] [CrossRef] [PubMed]
  23. Mason, T.M. The role of factors that regulate the synthesis and secretion of very-low-density lipoprotein by hepatocytes. Crit. Rev. Clin. Lab. Sci. 1998, 35, 461–487. [Google Scholar] [CrossRef] [PubMed]
  24. Apolipoproteins: the Apoproteins in Lipoproteins 2008. Available online: (accessed on 17 November 2015).
  25. Shaw, I.; Vanoort, R. Food Chemical Safety; Watson, D.H., Ed.; CRC Press: Leiden, The Netherlands; Woodhead Publishing Limited: Cambridge, UK, 2001; Chapter 10 Mycotoxins; Volume 1 Contaminants, pp. 239–245. [Google Scholar]
  26. Zain, Z.E. Impact of mycotoxins on humans and animals. J. Saudi Chem. Soc. 2011, 15, 129–144. [Google Scholar] [CrossRef]
  27. Plumlee, K.H.; Galey, F.D. Neurotoxic mycotoxins: A review of fungal toxins that cause neurological disease in large animals. J. Vet. Intern. Med. 1994, 8, 49–54. [Google Scholar] [CrossRef] [PubMed]
  28. Surai, P.F.; Mezes, M.; Vladimir, I.; Fisinin, V.I.; Fotina, T.I. Effects of mycotoxins on animal health: From oxidative stress to gene expression. Available online: (accessed on 27 August 2015).
  29. Ikegwuonu, F.I. The neurotoxicity of aflatoxin B1 in the rat. Toxicology 1983, 28, 247–259. [Google Scholar] [CrossRef]
  30. Roze, L.V.; Hong, S.-Y.; Linz, J.E. Aflatoxin biosynthesis: Current frontiers. Annu. Rev. Food Sci. Technol. 2013, 4, 293–311. [Google Scholar] [CrossRef] [PubMed]
  31. Doi, K.; Uetsuka, K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int. J. Mol. Sci. 2011, 12, 5213–5237. [Google Scholar] [CrossRef] [PubMed]
  32. Gentry, P.A.; Ross, M.L.; Bondy, G.S. Inhibitory effect of trichothecene mycotoxins on bovine platelets stimulated by platelet activating factor. Can. J. Vet. Res. 1987, 51, 490–494. [Google Scholar] [PubMed]
  33. Grandoni, K.; Gentry, P.; Holub, B.; Yagen, B. Comparative effects of trichothecene mycotoxins on bovine platelet function: Acetyl T-2 toxin, a more potent inhibitor than T-2 toxin. Mycotoxin Res. 1990, 6, 61–66. [Google Scholar] [CrossRef] [PubMed]
  34. Chattopadhyay, P.; Upadhyay, A.; Agnihotri, A.; Karmakar, S.; Ghoyary, D.; Veer, V. Hematoxicity of fusirium mycotoxin in experimental Sprague-Dawley rats. Toxicol. Int. 2013, 20, 25–29. [Google Scholar] [CrossRef] [PubMed]
  35. Ostry, V.; Malir, F.; Ruprich, J. Producers and important dietary sources of ochratoxin A and citrinin. Toxins 2013, 5, 1574–1586. [Google Scholar] [CrossRef] [PubMed]
  36. Paradells, S.; Rocamonde, B.; Llinares, C.; Herranz-Pérez, V.; Jimenez, M.; Garcia-Verdugo, J.M.; Zipancic, I.; Soria, J.M.; Garcia-Esparza, M.A. Neurotoxic effects of ochratoxin-A on the subventricular zone of adult mouse brain. J. Appl. Toxicol. 2015, 35, 737–751. [Google Scholar] [CrossRef] [PubMed]
  37. Sava, V.; Reunova, O.; Velasquez, A.; Sanchez-Ramos, J. Can low level exposure to ochratoxin-A cause Parkinsonism? J. Neurol. Sci. 2006, 249, 68–75. [Google Scholar] [CrossRef] [PubMed]
  38. Dias, I.H.; Polidori, M.C.; Griffiths, H.R. Hypercholesterolaemia-induced oxidative stress at the blood-brain barrier. Biochem. Soc. Trans. 2014, 42, 1001–1005. [Google Scholar] [CrossRef] [PubMed]
  39. Kalayci, R.; Kaya, M.; Uzun, H.; Bilgic, B.; Ahishali, B.; Arican, N.; Elmas, I.; Küçük, M. Influence of hypercholesterolemia and hypertension on the integrity of the blood-brain barrier in rats. Int. J. Neurosci. 2009, 119, 1881–904. [Google Scholar] [CrossRef] [PubMed]
  40. Tesoriere, L.; Attanzio, A.; Allegra, M.; Cilla, A.; Gentile, C.; Livrea, M.A. Oxysterol mixture in hypercholesterolemia-relevant proportion causes oxidative stress-dependent eryptosis. Cell. Physiol. Biochem. 2014, 34, 1075–1089. [Google Scholar] [CrossRef] [PubMed][Green Version]
  41. Kim, E.J.; Kim, B.-H.; Seo, H.S.; Lee, Y.J.; Kim, H.H.; Son, H.-H.; Choi, M.H. Cholesterol-induced non-alcoholic fatty liver disease and atherosclerosis aggravated by systemic inflammation. PLoS ONE 2014, 9, e9784. [Google Scholar] [CrossRef] [PubMed]
  42. Björkhem, I.; Heverin, M.; Leoni, V.; Meaney, S.; Diczfalusy, U. Oxysterols and Alzheimer’s disease. Acta Neurol. Scand. Suppl. 2006, 185, 43–49. [Google Scholar] [CrossRef] [PubMed]
  43. Poli, G.; Biasi, F.; Leonarduzzi, G. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol. 2013, 1, 125–130. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, H.; Eckel, R.H. What are lipoproteins doing in the brain? Trends Endocrinol. Metab. 2014, 25, 8–14. [Google Scholar] [CrossRef] [PubMed]
  45. Wolozin, B.; Brown, J., 3rd; Theisler, C.; Silberman, S. The cellular biochemistry of cholesterol and statins: Insights into the pathophysiology and therapy of Alzheimer’s disease. CNS Drug Rev. 2004, 10, 127–146. [Google Scholar] [CrossRef] [PubMed]
  46. Papassotiropoulos, A.; Lütjohann, D.; Bagli, M.; Locatelli, S.; Jessen, F.; Buschfort, R.; Ptok, U.; Björkhem, I.; von Bergmann, K.; Heun, R. 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia. J. Psychiatr. Res. 2002, 36, 27–32. [Google Scholar] [CrossRef]
  47. Tucsek, Z.; Toth, P.; Sosnowska, D.; Gautam, T.; Mitschelen, M.; Koller, A.; Szalai, G.; Sonntag, W.E.; Ungvari, Z.; Csiszar, A. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: Effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 1212–1226. [Google Scholar] [CrossRef] [PubMed]
  48. Jiang, X.; Guo, M.; Su, J.; Lu, B.; Ma, D.; Zhang, R.; Yang, L.; Wang, Q.; Ma, Y.; Fan, Y. Simvastatin blocks blood-brain barrier disruptions induced by elevated cholesterol both in vivo and in vitro. Int. J. Alzheimer’s Dis. 2012. [Google Scholar] [CrossRef] [PubMed]
  49. Goldwaser, E.L.; Acharya, N.K.; Nagele, R.G. Cerebrovascular and blood-brain barrier compromise: A mechanistic link between vascular disease and Alzheimer’s disease subtypes of neurocognitive disorders. J. Parkinsons Dis. Alzheimer’s Dis. 2015, 2, 10. [Google Scholar]
  50. Acharya, N.K.; Levin, E.C.; Clifford, P.M.; Han, M.; Tourtellotte, R.; Chamberlain, D.; Pollaro, M.; Coretti, N.J.; Kosciuk, M.C.; Nagele, E.P.; et al. Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: Beneficial effects of the LpPLA2 inhibitor darapladib. J. Alzheimer’s Dis. 2013, 35, 179–198. [Google Scholar]
  51. Campbell, A.W.; Thrasher, J.D.; Gray, M.R.; Vojdani, A. Mold and mycotoxins: Effects on the neurological and immune systems in humans. Adv. Appl. Microbiol. 2004, 55, 375–406. [Google Scholar] [PubMed]
  52. Maresca, M. From the gut to the brain: Journey and pathophysiological effects of the food-associated trichothecene mycotoxin deoxynivalenol. Toxins 2013, 5, 784–820. [Google Scholar] [CrossRef] [PubMed]
  53. Weidner, M.; Hüwel, S.; Ebert, F.; Schwerdtle, T.; Galla, H.-J.; Humpf, H.-U. Influence of T-2 and HT-2 toxin on the blood-brain barrier in vitro: New experimental hints for neurotoxic effects. PLoS ONE 2013, 8, e60484. [Google Scholar] [CrossRef] [PubMed]
  54. Jangula, A.; Murphy, E.J. Lipopolysaccharide-induced blood brain barrier permeability is enhanced by alpha-synuclein expression. Neurosci. Lett. 2013, 551, 23–27. [Google Scholar] [CrossRef] [PubMed]
  55. Xaio, H.; Banks, W.A.; Nieholf, M.L.; Morley, J.E. Effect of LPS on the permeability of the blood-brain barrier to insulin. Brain Res. 2001, 896, 36–42. [Google Scholar] [CrossRef]
  56. Qin, L.; Wu, X.; Block, M.L.; Liu, Y.; Breese, G.R.; Hong, J.S.; Knapp, D.J.; Crews, F.T. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007, 55, 453–462. [Google Scholar] [CrossRef] [PubMed]
  57. Lee, J.W.; Lee, Y.K.; Yuk, D.Y.; Choi, D.Y.; Ban, S.B.; Oh, K.W.; Hong, J.T. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of β-amyloid generation. J. Neuroinflamm. 2008, 5. [Google Scholar] [CrossRef] [PubMed]
  58. Huang, H.; Liu, T.; Rose, J.L.; Stevens, R.L.; Hoyt, D.G. Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet. J. Inflamm. 2007, 4. [Google Scholar] [CrossRef] [PubMed]
  59. Kim, K.-A.; Gu, W.; Lee, I.-A.; Joh, E.-H.; Kim, D.-H. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE 2012, 7, e47713. [Google Scholar] [CrossRef] [PubMed]
  60. Lee, C.Y. The Effect of High-fat diet-induced pathophysiological changes in the gut on obesity: What should be the ideal treatment? Clin. Transl. Gastroenterol. 2013, 4, e39. [Google Scholar] [CrossRef] [PubMed]
  61. Amar, J.; Burcelin, R.; Ruidavets, J.B.; Cani, P.D.; Fauvel, J.; Alessi, M.C.; Chamontin, B.; Ferriéres, J. Energy intake is associated with endotoxemia in apparently healthy men. Am. J. Clin. Nutr. 2008, 87, 1219–1223. [Google Scholar] [PubMed]
  62. Fenton, M.J.; Golenbock, D.T. LPS-binding proteins and receptors. J. Leukoc. Biol. 1998, 64, 25–32. [Google Scholar] [PubMed]
  63. Ciesielski, F.; Davis, B.; Rittig, M.; Bonev, B.B.; O’Shea, P. Receptor-independent interaction of bacterial lipopolysaccharide with lipid and lymphocyte membranes; the role of cholesterol. PLoS ONE 2012, 7, e38677. [Google Scholar] [CrossRef] [PubMed]
  64. Feingold, K.R.; Staprans, I.; Memon, R.A.; Moser, A.H.; Shigenaga, J.K.; Doerrler, W. Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: Low doses stimulate hepatic triglyceride production while high doses inhibit clearance. J. Lipid Res. 1992, 33, 1765–1776. [Google Scholar] [PubMed]
  65. Miele, L.; Marrone, G.; Lauritano, C.; Cefalo, C.; Gasbarrini, A.; Day, C. Gut-liver axis and microbiota in NAFLD: Insight pathophysiology for novel therapeutic target. Curr. Pharm. Des. 2013, 19, 5314–5324. [Google Scholar] [CrossRef] [PubMed]
  66. Le Roy, T.; Llopis, M.; Lepage, P.; Bruneau, A.; Rabot, S.; Bevilacqua, C. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013, 62, 1787–1794. [Google Scholar]
  67. Alisi, A.; Ceccarelli, S.; Panera, N.; Nobili, V. Causative role of gut microbiota in non-alcoholic fatty liver disease pathogenesis. Front. Cell. Infect. Microbiol. 2012, 2. [Google Scholar] [CrossRef] [PubMed]
  68. Duseja, A.; Chawla, Y.K. Obesity and NAFLD: The role of bacteria and microbiota. Clin. Liver Dis. 2014, 18, 59–71. [Google Scholar] [CrossRef] [PubMed]
  69. Martins, I.J. LPS Regulates apolipoprotein E and Aβ Interactions with effects on acute phase proteins and amyloidosis. Adv. Aging Res. 2015, 4, 69–77. [Google Scholar] [CrossRef]
  70. Martins, I.J. Unhealthy diets determine benign or toxic amyloid beta states and promote brain amyloid beta aggregation. Austin J. Clin. Neurol. 2015, 2, 1060–1066. [Google Scholar]
  71. Martins, I.J. Diabetes and cholesterol dyshomeostasis involve abnormal α-synuclein and amyloid beta transport in neurodegenerative diseases. Austin Alzheimer’s J. Parkinsons Dis. 2015, 2, 1020–1028. [Google Scholar]
  72. Deane, R.; Bell, R.D.; Sagare, A.; Zlokovic, B.V. Clearance of amyloid-beta peptide across the blood-brain barrier: Implication for therapies in Alzheimer’s disease. CNS Neurol. Disord. Drug Targets 2009, 8, 16–30. [Google Scholar] [CrossRef] [PubMed]
  73. Castellano, J.M.; Deane, R.; Gottesdiener, A.J.; Verghese, P.B.; Stewart, F.R.; West, T.; Paoletti, A.C.; Kasper, T.R.; DeMattos, R.B.; Zlokovic, B.V.; et al. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis. Proc. Natl. Acad. Sci. USA 2012, 109, 15502–15507. [Google Scholar] [CrossRef] [PubMed]
  74. Basak, J.M.; Verghese, P.B.; Yoon, H.; Kim, J.; Holtzman, D.M. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes. J. Biol. Chem. 2012, 287, 13959–13971. [Google Scholar] [CrossRef] [PubMed]
  75. Riley, R.T.; Goeger, D.E.; Hinton, D.M. Microbial Toxins in Foods and Feeds; Chapter Mycotoxin-Induced Alterations in Ion Transport across Cell Membranes; Pohland, A.E., Ed.; Plenum Press: New York, NY, USA, 1990. [Google Scholar]
  76. Kaplan, R.; Gan, X.; Menke, J.G.; Wright, S.D.; Cai, T.Q. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J. Lipid Res. 2002, 43, 952–959. [Google Scholar] [PubMed]
  77. Martin, S.; Parton, R.G. Caveolin, cholesterol, and lipid bodies. Semin. Cell Dev. Biol. 2005, 16, 163–174. [Google Scholar] [CrossRef] [PubMed]
  78. Frank, P.G.; Cheung, M.W.; Pavlides, S.; Llaverias, G.; Park, D.S.; Lisanti, M.P. Caveolin-1 and regulation of cellular cholesterol homeostasis. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H677–H686. [Google Scholar] [CrossRef] [PubMed]
  79. Fantini, J.; Barrantes, F.J. How cholesterol interacts with membrane proteins: An exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains. Front. Physiol. 2013, 4. [Google Scholar] [CrossRef] [PubMed][Green Version]
  80. Hulce, J.J.; Cognetta, A.B.; Niphakis, M.J.; Tully, S.E.; Cravatt, B.F. Extracting intracellular diffusive states and transition rates from single-molecule tracking data Proteome-wide mapping of cholesterol-interacting proteins in mammalian cells. Nat. Methods 2013, 10, 259–264. [Google Scholar] [CrossRef] [PubMed]
  81. Epand, R.M. Review cholesterol and the interaction of proteins with membrane domains. Prog. Lipid Res. 2006, 45, 279–294. [Google Scholar] [CrossRef] [PubMed]
  82. Gimpl, G. Cholesterol-protein interaction: Methods and cholesterol reporter molecules. Subcell. Biochem. 2010, 51, 1–45. [Google Scholar] [PubMed]
  83. Parton, R.G.; Simons, K. The multiple faces of caveolae. Nat. Rev. Mol. Cell Biol. 2007, 8, 185–194. [Google Scholar] [CrossRef] [PubMed]
  84. Parton, R.G. Caveolae Meet Endosomes: A Stable Relationship? Dev. Cell 2004, 7, 458–460. [Google Scholar] [CrossRef] [PubMed]
  85. Mundy, D.I.; Li, W.P.; Luby-Phelps, K.; Anderson, R.G. Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content. Mol. Biol. Cell 2012, 23, 864–880. [Google Scholar] [CrossRef] [PubMed]
  86. Frank, P.G.; Galbiati, F.; Volonte, D.; Razani, B.; Cohen, D.E.; Marcel, Y.L.; Lisanti, M.P. Influence of caveolin-1 on cellular cholesterol efflux mediated by high-density lipoproteins. Am. J. Physiol. Cell Physiol. 2001, 280, C1204–C1214. [Google Scholar] [PubMed]
  87. Matveev, S.; Uittenbogaard, A.; van der Westhuyzen, D.; Smart, E.J. Caveolin-1 negatively regulates SR-BI mediated selective uptake of high-density lipoprotein-derived cholesteryl ester. Eur. J. Biochem. 2001, 268, 5609–5616. [Google Scholar] [CrossRef] [PubMed]
  88. Hailstones, D.; Sleer, L.S.; Parton, R.G.; Stanley, K.K. Regulation of caveolin and caveolae by cholesterol in MDCK cells. J. Lipid Res. 1998, 39, 369–379. [Google Scholar] [PubMed]
  89. Lei, M.G.; Tan, X.; Qureshi, N.; Morrison, D.C. Regulation of cellular caveolin-1 protein expression in murine macrophages by microbial products. Infect. Immun. 2005, 73, 8136–8143. [Google Scholar] [CrossRef] [PubMed]
  90. Medina, F.A.; de Almeida, C.J.; Dew, E.; Li, J.-W.; Bonuccelli, G.; Williams, T.M.; Cohen, A.W.; Pestell, R.G.; Frank, P.J.; Tanowitz, H.B.; et al. Caveolin-1-deficient mice show defects in innate immunity and inflammatory immune response during salmonella enterica serovar typhimurium infection. Infect. Immun. 2006, 74, 6665–6674. [Google Scholar] [CrossRef] [PubMed]
  91. Henning, M.F.; Garda, H.A.; Bakas, L. Biophysical characterization of interaction between apolipoprotein A-I and bacterial lipopolysaccharide. Cell. Biochem. Biophys. 2006, 44, 490–496. [Google Scholar] [CrossRef]
  92. Wang, Y.; Zhu, X.; Wu, G.; Shen, L.; Chen, B. Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice. J. Lipid Res. 2008, 49, 1640–1645. [Google Scholar] [CrossRef] [PubMed]
  93. Gupta, H.; Dai, L.; Datta, G.; Garber, D.W.; Grenett, H.; Li, Y.; Mishra, V.; Palgunachari, M.N.; Handattu, S.; Gianturco, S.H.; et al. Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide. Circ. Res. 2005, 97, 236–243. [Google Scholar] [CrossRef] [PubMed]
  94. Wang, N.; Silver, D.L.; Thiele, C.; Tall, A.R. ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J. Biol. Chem. 2001, 276, 23742–23747. [Google Scholar] [CrossRef] [PubMed]
  95. Burns, M.P.; Vardanian, L.; Pajoohesh-Ganji, A.; Wang, L.; Cooper, M.; Harris, D.C.; Duff, K.; Rebeck, G.W. The effects of ABCA1 on cholesterol efflux and Aβ levels in vitro and in vivo. J. Neurochem. 2006, 98, 792–800. [Google Scholar] [CrossRef] [PubMed]
  96. Sahoo, D.; Trischuk, T.C.; Chan, T.; Drover, V.A.B.; Ho, S.; Chimini, G.; Agellon, L.B.; Agnihotri, R.; Francis, A.; Lehner, R. ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes. J. Lipid Res. 2004, 45, 1122–1131. [Google Scholar] [CrossRef] [PubMed]
  97. Butterfield, D.A.; Castegna, A.; Lauderback, C.M.; Drake, J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol. Aging 2002, 23, 655–664. [Google Scholar] [CrossRef]
  98. Oates, J.; Watts, A. Uncovering the intimate relationship between lipids, cholesterol and GPCR activation. Curr. Opin. Struct. Biol. 2011, 21, 802–807. [Google Scholar] [CrossRef] [PubMed]
  99. Paila, Y.D.; Chattopadhyay, A. Membrane cholesterol in the function and organization of G-protein coupled receptors. Subcell. Biochem. 2010, 51, 439–466. [Google Scholar] [PubMed]
  100. Sengupta, D.; Chattopadhyay, A. Molecular dynamics simulations of GPCR-cholesterol interaction: An emerging paradigm. Biochim. Biophys. Acta 2015, 1848, 1775–1782. [Google Scholar] [CrossRef] [PubMed]
  101. Thathiah, A.; de Strooper, B. G protein—Coupled receptors, cholinergic dysfunction, and Aβ toxicity in Alzheimer’s disease. Sci. Signal. 2009, 2. [Google Scholar] [CrossRef] [PubMed]
  102. Thathiah, A.; de Strooper, B. The role of G protein-coupled receptors in the pathology of Alzheimer’s disease. Nat. Rev. Neurosci. 2011, 12, 73–87. [Google Scholar] [CrossRef] [PubMed]
  103. Chini, B.; Parenti, M. G-protein coupled receptors in lipid rafts and caveolae: How, when and why do they go there? J. Mol. Endocrinol. 2004, 32, 325–338. [Google Scholar] [CrossRef] [PubMed]
  104. Lin, Y.C.; Ma, C.; Hsu, W.C.; Lo, H.F.; Yang, V.C. Molecular interaction between caveolin-1 and ABCA1 on high-density lipoprotein-mediated cholesterol efflux in aortic endothelial cells. Cardiovasc. Res. 2007, 75, 575–583. [Google Scholar] [CrossRef] [PubMed]
  105. Cohen, A.W.; Combs, T.P.; Scherer, P.E.; Lisanti, M.P. Role of caveolin and caveolae in insulin signaling and diabetes. Am. J. Physiol. Endocrinol. Metab. 2003, 285, E1151–E1160. [Google Scholar] [CrossRef] [PubMed]
  106. Yamamoto, M.; Toya, Y.; Schwencke, C.; Lisanti, M.P.; Myers, M.G.; Ishikawa, Y. Caveolin is an activator of insulin receptor signaling. J. Biol. Chem. 1998, 273, 26962–26968. [Google Scholar] [CrossRef] [PubMed]
  107. Nystrom, F.H.; Chen, H.; Cong, L.N.; Li, Y.; Quon, M.J. Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. Mol. Endocrinol. 1999, 13, 2013–2024. [Google Scholar] [CrossRef] [PubMed]
  108. Cohen, A.W.; Razani, B.; Wang, X.B.; Combs, T.P.; Williams, T.M.; Scherer, P.E.; Lisanti, M.P. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am. J. Physiol. Cell Physiol. 2003, 285, C222–C235. [Google Scholar] [CrossRef] [PubMed]
  109. Head, B.P.; Peart, J.N.; Panneerselvam, M.; Yokoyama, T.; Pearn, M.L.; Niesman, I.R.; Bonds, J.A.; Schilling, J.M.; Miyanohara, A.; Headrick, J.; et al. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS ONE 2010, 5, e15697. [Google Scholar] [CrossRef] [PubMed]
  110. Van Helmond, Z.K.; Miners, J.S.; Bednall, E.; Chalmers, K.A.; Zhang, Y.; Wilcock, G.K.; Love, S.; Khoe, P.G. Caveolin-1 and -2 and their relationship to cerebral amyloid angiopathy in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 2007, 33, 317–327. [Google Scholar] [CrossRef] [PubMed]
  111. Gaudreault, S.B.; Dea, D.; Poirier, J. Increased caveolin-1 expression in Alzheimer’s disease brain. Neurobiol. Aging 2004, 25, 753–759. [Google Scholar] [CrossRef] [PubMed]
  112. Martins, I.J.; Gupta, V.; Wilson, A.C.; Fuller, S.J.; Martins, R.N. Interactions between apo E and amyloid beta and their relationship to nutriproteomics and neurodegeneration. Curr. Proteom. 2014, 11, 173–183. [Google Scholar]
  113. Haziot, A.; Lin, X.Y.; Zhang, F.; Goert, S.M. Cutting edge: The induction of acute phase proteins by lipopolysaccharide uses a novel pathway that is CD14-independent. J. Immunol. 1998, 160, 2570–2572. [Google Scholar] [PubMed]
  114. Liu, M.; Bing, G. Lipopolysaccharide animal models for Parkinson’s disease. Parkinson’s Dis. 2011, 2011, 327089. [Google Scholar] [CrossRef] [PubMed]
  115. Spitzer, P.; Herrmann, M.; Klafki, H.W.; Smirnov, A.; Lewczuk, P.; Kornhuber, J. Phagocytosis and LPS alter the maturation state of β-amyloid precursor protein and induce different Aβ peptide release signatures in human mononuclear phagocytes. J. Neuroinflamm. 2010, 7. [Google Scholar] [CrossRef] [PubMed]
  116. Bate, C.; Veerhuis, R.; Eikelenboom, P.; Williams, A. Microglia kill amyloid-β1-42 damaged neurons by a CD14-dependent process. Neuroreport 2004, 15, 1427–1430. [Google Scholar] [CrossRef] [PubMed]
  117. Erickson, M.A.; Hartvigson, P.E.; Morofuji, Y.; Owen, J.B.; Butterfield, D.A.; Banks, W.A. Lipopolysaccharide impairs amyloid β efflux from brain: Altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. J. Neuroinflamm. 2012, 9. [Google Scholar] [CrossRef]
  118. Murray, C.L.; Skelly, D.T.; Cunningham, C. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1β and IL-6. J. Neuroinflamm. 2011, 8. [Google Scholar] [CrossRef] [PubMed]
  119. Waché, Y.J.; Hbabi-Haddioui, L.; Guzylack-Piriou, L.; Belkhelfa, H.; Roques, C.; Oswald, I.P. The mycotoxin deoxynivalenol inhibits the cell surface expression of activation markers in human macrophages. Toxicology 2009, 262, 239–244. [Google Scholar] [CrossRef] [PubMed]
  120. Garwood, C.J.; Pooler, A.M.; Atherton, J.; Hanger, D.P.; Noble, W. Astrocytes are important mediators of Aβ-inducedneurotoxicity and tau phosphorylation in primary culture. Cell Death Dis. 2011, 202, e167. [Google Scholar] [CrossRef] [PubMed]
  121. Nagele, R.G.; D’Andrea, M.R.; Lee, H.; Venkataraman, V.; Wang, H.Y. Astrocytes accumulate Aβ 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003, 971, 197–209. [Google Scholar] [CrossRef]
  122. Wyss-Coray, T.; Loike, J.D.; Brionne, T.C.; Lu, E.; Anankov, R.; Yan, F.; Silverstein, S.C.; Husemann, J. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat. Med. 2003, 9, 453–457. [Google Scholar] [CrossRef] [PubMed]
  123. Canepa, E.; Borghi, R.; Viña, J.; Traverso, N.; Gambini, J.; Domenicotti, C.; Marinari, U.M.; Poli, G.; Pronzato, M.A.; Ricciarelli, R. Cholesterol and amyloid-β: Evidence for a cross-talk between astrocytes and neuronal cells. J. Alzheimer’s Dis. 2011, 25, 645–653. [Google Scholar] [CrossRef]
  124. Danik, M.; Champagne, D.; Petit-Turcotte, C.; Beffert, U.; Poirier, J. Brain lipoprotein metabolism and its relation to neurodegenerative disease. Crit. Rev. Neurobiol. 1999, 13, 357–407. [Google Scholar] [PubMed]
  125. Jänis, M.T.; Metso, J.; Lankinen, H.; Strandin, T.; Olkkonen, V.M.; Rye, K.A.; Jauhiainen, M.; Ehnholm, C. Apolipoprotein E activates the low-activity form of human phospholipid transfer protein. Biochem. Biophys. Res. Commun. 2005, 331, 333–340. [Google Scholar] [CrossRef] [PubMed]
  126. Oram, J.F.; Wolfbauer, G.; Tang, C.; Davidson, W.; Albers, J.J. An amphipathic helical region of the N-terminal barrel of phospholipid transfer protein is critical for ABCA1-dependent cholesterol efflux. J. Biol. Chem. 2008, 283, 11541–11549. [Google Scholar] [CrossRef] [PubMed]
  127. Lim, W.F.L.; Martins, I.J.; Martins, R.N. Lipid metabolism and lipidomics: An emerging frontier in biology. J. Genet. Genom. 2014, 41, 261–274. [Google Scholar] [CrossRef] [PubMed]
  128. Desrumaux, C.; Pisoni, A.; Meunier, J.; Deckert, V.; Athias, A.; Perrier, V.; Villard, V.; Lagrost, L.; Verdier, J.M.; Maurice, T. Increased amyloid-β peptide-induced memory deficits in phospholipid transfer protein (PLTP) gene knockout mice. Neuropsychopharmacology 2013, 38, 817–825. [Google Scholar] [CrossRef] [PubMed]
  129. Ye, Q.; Lei, H.; Fan, Z.; Zheng, W.; Zheng, S. Difference in LDL receptor feedback regulation in macrophages and vascular smooth muscle cells: Foam cell transformation under inflammatory stress. Inflammation 2014, 37, 555–565. [Google Scholar] [CrossRef] [PubMed]
  130. Yun, S.; Urbanc, B.; Cruz, L.; Bitan, G.; Teplow, D.B.; Stanley, H.E. Role of electrostatic interactions in amyloid β-protein (Aβ) oligomer formation: A discrete molecular dynamics study. Biophys. J. 2007, 92, 4064–4077. [Google Scholar] [CrossRef] [PubMed]
  131. Surai, P.; Mezes, M.; Fotina, T.; Denev, S.D. Modern Dietary Fat Intakes in Disease Promotion; De Meester, F., Zibadi, S., Watson, R.R., Eds.; Medical: New York, NY, USA, 2010; Chapter Mycotoxin in Human Diet: A Hidden Danger; pp. 275–375. [Google Scholar]
  132. Burghardt, R.C.; Barhoumi, R.; Lewis, E.H.; Bailey, R.H.; Pyle, K.A.; Clement, B.A.; Phillips, T.D. Patulin-induced cellular toxicity: A vital fluorescence study. Toxicol. Appl. Pharmacol. 1992, 112, 235–244. [Google Scholar] [CrossRef]
  133. Riley, R.T.; Showker, J.L. The mechanism of patulin’s cytotoxicity and the antioxidant activity of indole tetramic acids. Toxicol. Appl. Pharmacol. 1991, 109, 108–126. [Google Scholar] [CrossRef]
  134. Horváth, E.; Papp, G.; Belágyi, J.; Gazdag, Z.; Vágvölgyi, C.; Pesti, M. In vivo direct patulin-induced fluidization of the plasma membrane of fission yeast Schizosaccharomyces pombe. Food Chem. Toxicol. 2010, 48, 1898–1904. [Google Scholar] [CrossRef] [PubMed]
  135. Riley, R.T.; Hinton, D.M.; Showker, J.L.; Rigsby, W.; Norred, W.P. Chronology of patulin-induced alterations in membrane function of cultured renal cells, LLC-PK. Toxicol. Appl. Pharmacol. 1990, 102, 128–141. [Google Scholar] [CrossRef]
  136. Ziprin, R.L.; Holt, P.S.; Mortensen, R.F. T-2 toxin effects on the serum amyloid P-component (SAP) response of Listeria monocytogenes- and Salmonella typhimurium-infected mice. Toxicol. Lett. 1987, 39, 177–184. [Google Scholar] [CrossRef]
  137. Di Giuseppe, R.; Bertuzzi, T.; Rossi, F.; Rastelli, S.; Mulazzi, A.; Capraro, J.; de Curtis, A.; Iacoviello, L.; Pietri, A. Plasma ochratoxin A levels, food consumption, and risk biomarkers of a representative sample of men and women from the Molise region in Italy. Eur. J. Nutr. 2012, 51, 851–860. [Google Scholar] [CrossRef] [PubMed]
  138. Bi, B.T.; Lin, H.B.; Cheng, Y.F.; Zhou, H.; Lin, T.; Zhang, M.Z.; Li, T.J.; Xu, J.P. Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer’s disease. Neurochem. Int. 2012, 60, 257–266. [Google Scholar] [CrossRef] [PubMed]
  139. Gopalakrishnan, V.K.; Sakthisekaran, D. Effect of patulin on albumin fraction of plasma proteins studied in rats. Biochem. Int. 1991, 25, 461–475. [Google Scholar] [PubMed]
  140. Salsbury, E.R.; Poole, L.B.; Fetrow, J.S. Electrostatics of cysteine residues in proteins: Parameterization and validation of a simple model. Proteins 2012, 80, 1–17. [Google Scholar] [CrossRef] [PubMed]
  141. Van Geest, M.; Lolkema, J.S. Membrane topology and insertion of membrane proteins: Search for topogenic signals. Microbiol. Mol. Biol. Rev. 2000, 64, 13–33. [Google Scholar] [CrossRef] [PubMed]
  142. Hozoji, M.; Kimura, Y.; Kioka, N.; Ueda, K. Formation of two intramolecular disulfide bonds is necessary for apoA-I-dependent cholesterol efflux mediated by ABCA1. J. Biol. Chem. 2009, 284, 11293–11300. [Google Scholar] [CrossRef] [PubMed]
  143. Nagao, K.; Tomioka, M.; Ueda, K. Function and regulation of ABCA1—Membrane meso-domain organization and reorganization. FEBS J. 2011, 278, 3190–3203. [Google Scholar] [CrossRef] [PubMed]
  144. Qu, S.J.; Fan, H.Z.; Kilinc, C.; Pownall, H.J. Role of cysteine residues in human plasma phospholipid transfer protein. J. Protein Chem. 1999, 18, 193–198. [Google Scholar] [CrossRef] [PubMed]
  145. Dietzen, D.J.; Hastings, W.R.; Lublin, D.M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 1995, 270, 6838–6842. [Google Scholar] [PubMed]
  146. Rubenstein, L.A.; Lanzarab, R.G. Activation of G protein-coupled receptors entails cysteine modulation of agonist binding. J. Mol. Struct.: THEOCHEM 1998, 430, 57–71. [Google Scholar] [CrossRef]
  147. Olivella, M.; Caltabiano, G.; Cordomí, A. The role of Cysteine 6.47 in class A GPCRs. BMC Struct. Biol. 2013, 13. [Google Scholar] [CrossRef] [PubMed]
  148. Moriyama, K.; Sasaki, J.; Takada, Y.; Matsunaga, A.; Fukui, J.; Albers, J.J.; Arakawa, K. A cysteine-containing truncated apo A-I variant associated with HDL deficiency. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 1416–1423. [Google Scholar] [CrossRef] [PubMed]
  149. Oda, M.N.; Bielicki, J.K.; Berger, T.; Forte, T.M. Cysteine substitutions in apolipoprotein A-I primary structure modulate paraoxonase activity. Biochemistry 2001, 40, 1710–1718. [Google Scholar] [CrossRef] [PubMed]
  150. Daly, N.L.; Scanlon, M.J.; Djordjevic, J.T.; Kroon, P.A.; Smith, R. Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA 1995, 92, 6334–6338. [Google Scholar] [CrossRef] [PubMed][Green Version]
  151. Lillis, A.P.; van Duyn, L.B.; Murphy-Ullrich, J.-E.; Strickland, D.K. The low density lipoprotein receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 2008, 88, 887–918. [Google Scholar] [CrossRef] [PubMed]
  152. Ivaturi, S.; Wooten, C.J.; Nguyen, M.D.; Ness, G.C.; Lopez, D. Distribution of the LDL receptor within clathrin-coated pits and caveolae in rat and human liver. Biochem. Biophys. Res. Commun. 2014, 445, 422–427. [Google Scholar] [CrossRef] [PubMed]
  153. Alves, I.; Oliveira, N.G.; Laires, A.; Rodrigues, A.S.; Rueff, J. Induction of micronuclei and chromosomal aberrations by the mycotoxin patulin in mammalian cells: Role of ascorbic acid as a modulator of patulin clastogenicity. Mutagenesis 2000, 15, 229–234. [Google Scholar] [CrossRef] [PubMed]
  154. Song, E.; Su, C.; Fu, J.; Xia, X.; Yang, S.; Xiao, C.; Lu, B.; Chen, H.; Sun, Z.; Wu, S.; et al. Selenium supplementation shows protective effects against patulin-induced brain damage in mice via increases in GSH-related enzyme activity and expression. Life Sci. 2014, 109, 37–43. [Google Scholar] [CrossRef] [PubMed]
  155. Fliege, R.I.; Metzler, M. The mycotoxin patulin induces intra- and inter-molecular protein crosslinks in vitro involving cysteine, lysine, and histidine side chains, and alpha-amino groups. Chem. Biol. Interact. 1999, 123, 85–103. [Google Scholar] [CrossRef]
  156. Takai, E.; Uda, K.; Yoshida, T.; Zako, T.; Maeda, M.; Shiraki, K. Cysteine inhibits the fibrillisation and cytotoxicity of amyloid-β 40 and 42: Implications for the contribution of the thiophilic interaction. Phys. Chem. Chem. Phys. 2014, 16, 3566–3572. [Google Scholar] [CrossRef] [PubMed]
  157. Liao, S.-M.; Du, Q.-S.; Meng, J.-Z.; Pang, Z.-W.; Huang, R.-B. The multiple roles of histidine in protein interactions. Chem. Cent. J. 2013, 7. [Google Scholar] [CrossRef] [PubMed]
  158. Nguyen, K.V.; Gendrault, J.L.; Wolff, C.M. Poly-l-lysine dissolves fibrillar aggregation of the Alzheimer β-amyloid peptide in vitro. Biochem. Biophys. Res. Commun. 2002, 291, 764–768. [Google Scholar] [CrossRef] [PubMed]
  159. Sinha, S.; Lopes, D.H.; Bitan, G. A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity. ACS Chem. Neurosci. 2012, 3, 473–481. [Google Scholar] [CrossRef] [PubMed]
  160. Smith, D.G.; Ciccotosto, G.D.; Tew, D.J.; Perez, K.; Curtain, C.C.; Boas, J.F.; Masters, C.L.; Cappai, R.; Barnham, K.J. Histidine 14 modulates membrane binding and neurotoxicity of the Alzheimer’s disease amyloid-beta peptide. J. Alzheimer’s Dis. 2010, 19, 1387–1400. [Google Scholar]
  161. Herskovits, A.Z.; Guarente, L. SIRT1 in Neurodevelopment and Brain Senescence. Neuron 2014, 8, 471–483. [Google Scholar] [CrossRef] [PubMed]
  162. Tang, B.L.; Chua, C.E.L. SIRT1 and neuronal diseases. Mol. Asp. Med. 2008, 29, 187–200. [Google Scholar] [CrossRef] [PubMed]
  163. Guarente, L. Sirtuins in Aging and Disease. Cold Spring Harb. Symp. Quant. Biol. 2007, 72, 483–488. [Google Scholar] [CrossRef] [PubMed]
  164. Hansen, M.K.; Connolly, T.M. Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. Curr. Opin. Investig. Drugs 2008, 9, 247–255. [Google Scholar] [PubMed]
  165. Harrison, C. Neurodegenerative disorders: A neuroprotective role for Sirtuin 1. Nat. Rev. Drug Discov. 2012, 11. [Google Scholar] [CrossRef]
  166. Kawada, T.; Goto, T.; Hirai, S.; Kang, M.S.; Uemura, T.; Yu, R.; Takahashi, N. Dietary regulation of nuclear receptors in obesity-related metabolic syndrome. Asia Pac. J. Clin. Nutr. 2008, 17, 126–130. [Google Scholar] [PubMed]
  167. Martins, I.J. Nutritional Diets Accelerate Amyloid Beta Metabolism and Prevent the Induction of Chronic Diseases and Alzheimer’s Disease, 1st ed.; Photon ebooks: Quebec, Canada, 2015; pp. 1–48. [Google Scholar]
  168. Zee, R.S.; Pimentel, D.R.; Hou, X.L.; Zang, M.; Yao, C.X.; O’Connor, P.B.; Bachschmid, M.M.; Cohen, R.A. Sirtuin-1 zinc thiolate center is a direct molecular target of oxidants. In Proceedings of the Society for Free Radical Biology and Medicine’s 15th Annual Meeting, Indianapolis, IN, USA, 19–23 November 2008; Published in Free Radical Biology and Medicine. Volume 45. Supplement S76.
  169. Mori, H.; Kawai, K.; Ohbayashi, F.; Kuniyasu, T.; Yamazaki, M.; Hamasaki, T.; Williams, G.M. Genotoxicity of a variety of mycotoxins in the hepatocyte primary culture/DNA repair test using rat and mouse hepatocytes. Cancer Res. 1984, 44, 2918–2923. [Google Scholar] [PubMed]
  170. Martins, I.J.; Lim, W.L.F.; Wilson, A.; Laws, S.; Martins, R.N. The acceleration of aging and Alzheimer’s disease through the biological mechanisms behind obesity and type II diabetes. Health 2013, 5, 913–920. [Google Scholar] [CrossRef]
  171. Dawson, V.L.; Dawson, T.M. Nitric oxide neurotoxicity. J. Chem. Neuroanat. 1996, 10, 179–190. [Google Scholar] [CrossRef]
  172. Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D.A.; Stella, A.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity. Nat. Rev. Neurosci. 2007, 8, 766–775. [Google Scholar] [CrossRef] [PubMed]
  173. Kumar, A.; Chen, S.H.; Kadiiska, M.B.; Hong, J.S.; Zielonka, J.; Kalyanaraman, B.; Mason, R.P. Inducible nitric oxide synthase is key to peroxynitrite-mediated, LPS-induced protein radical formation in murine microglial BV2 cells. Free Radic. Biol. Med. 2014, 73, 51–59. [Google Scholar] [CrossRef] [PubMed]
  174. Yoo, B.K.; Choi, J.W.; Shin, C.-Y.; Jeon, S.J.; Park, S.J.; Cheong, J.H.; Han, S.Y.; Ryu, J.R.; Song, M.R.; Ko, K.H.; et al. Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-γ-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase. Neurochem. Int. 2008, 52, 1188–1197. [Google Scholar] [CrossRef] [PubMed]
  175. Shao, D.; Fry, J.L.; Han, J.; Hou, X.; Pimentel, D.R.; Matsui, R.; Cohen, R.A.; Bachschmid, M.M. A redox-resistant sirtuin-1 mutant protects against hepatic metabolic and oxidant stress. J. Biol. Chem. 2014, 289, 7293–7306. [Google Scholar] [CrossRef] [PubMed]
  176. Martins, I.J. Nutritional and genotoxic stress contributes to diabetes and neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. In Frontiers in Clinical Drug Research—CNS and Neurological Disorders; Atta-ur-Rahman, Ed.; Bentham Science Publishers: Cambridge, UK, 2015; Volume 35, pp. 158–192. [Google Scholar]
  177. Martins, I.J. Unhealthy Nutrigenomic Diets Accelerate NAFLD and Adiposity in Global communities. J. Mol. Genet. Med. 2015, 9, 1–11. [Google Scholar]
  178. Bist, A.; Fielding, C.J.; Fielding, P.E. p53 regulates caveolin gene transcription, cell cholesterol, and growth by a novel mechanism. Biochemistry 2000, 39, 1966–1972. [Google Scholar] [CrossRef] [PubMed]
  179. Galbiati, F.; Volonte, D.; Liu, J.; Capozza, F.; Frank, P.G.; Zhu, L.; Pestell, R.G.; Lisanti, M.P. Caveolin-1 expression negatively regulates cell cycle progression by inducing G0/G1 arrest via a p53/p21WAF1/Cip1-dependent mechanism. Mol. Biol. Cell 2001, 12, 2229–2244. [Google Scholar] [CrossRef] [PubMed]
  180. Volonte, D.; Zou, H.; Bartholomew, J.N.; Liu, Z.; Morel, P.A.; Galbiati, F. Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6). J. Biol. Chem. 2015, 290, 4202–4214. [Google Scholar] [CrossRef] [PubMed]
  181. Martins, I.J. Nutrition increases Survival and Reverses NAFLD and Alzheimers disease; Ebook Project; Jones, E., Ed.; GmbH & Co. KG.: Saarbrucken, Germany, 2015. [Google Scholar]
  182. Kitagawa, T.; Yokoyama, Y.; Kokuryo, T.; Nagino, M. Protective effects of l-cysteine against LPS-induced liver injuries. FASEB J. 2015, 29. [Google Scholar]
  183. Deng, J.; Huang, Q.; Wang, F.; Liu, Y.; Wang, Z.; Wang, Z.; Zhang, Q.; Lei, B.; Cheng, Y. The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles. J. Mol. Neurosci. 2012, 46, 677–687. [Google Scholar] [CrossRef] [PubMed]
  184. Zhao, Y.L.; Song, J.N.; Zhang, M. Role of caveolin-1 in the biology of the blood-brain barrier. Rev. Neurosci. 2014, 25, 247–254. [Google Scholar] [CrossRef] [PubMed]
  185. Madeira, A.; Yang, J.; Zhang, X.; Vikeved, E.; Nilsson, A.; Andrén, P.E.; Svenningsson, P. Caveolin-1 interacts with α-synuclein and mediates toxic actions of cellular α-synuclein overexpression. Neurochem. Int. 2011, 59, 280–289. [Google Scholar] [CrossRef] [PubMed]
  186. Hashimoto, M.; Takenouchi, T.; Rockenstein, E.; Masliah, E. α-Synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: Role in the pathogenesis of Parkinson’s disease. J. Neurochem. 2003, 85, 1468–1479. [Google Scholar] [CrossRef] [PubMed]
  187. Martins, I.J.; Vilchèze, C.; Mortimer, B.C.; Bittman, R.; Redgrave, T.G. Sterol side chain length and structure affect the clearance of chylomicron-like lipid emulsions in rats and mice. J. Lipid Res. 1998, 39, 302–312. [Google Scholar] [PubMed]
  188. Pfister, J.A.; Ma, C.; Morrison, B.E.; D’Mello, S.R. Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS ONE 2008, 3, e4090. [Google Scholar] [CrossRef] [PubMed]
  189. Akama, K.T.; Albanese, C.; Pestell, R.G.; van Eldik, L.J. Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NFκB-dependent mechanism. Proc. Natl. Acad. Sci. USA 1998, 95, 5795–5800. [Google Scholar] [CrossRef] [PubMed]
  190. Keil, U.; Bonert, A.; Marques, C.A.; Strosznajder, J.B.; Müller-Spahn, F.; Müller, W.E.; Eckert, A. Elevated nitric oxide production mediates β-amyloid-induced mitochondria failure. Pol. J. Pharmacol. 2004, 56, 631–634. [Google Scholar] [PubMed]
  191. Xiang, W.; Menges, S.; Schlachetzki, J.C.; Meixner, H.; Hoffmann., A.C.; Schlötzer-Schrehardt, U.; Becker, C.M.; Winkler, J.; Klucken, J. Posttranslational modification and mutation of histidine 50 trigger α synuclein aggregation and toxicity. Mol. Neurodegener. 2015, 10, 1–16. [Google Scholar] [CrossRef] [PubMed]
  192. Zhou, W.; Freed, C.R. Tyrosine-to-cysteine modification of human alpha-synuclein enhances protein aggregation and cellular toxicity. J. Biol. Chem. 2004, 279, 10128–10135. [Google Scholar] [CrossRef] [PubMed]
  193. Williamson, M.P.; Suzuki, Y.; Bourne, N.T.; Asakura, T. Binding of amyloid β-peptide to ganglioside micelles is dependent on histidine-13. Biochem. J. 2006, 397, 483–490. [Google Scholar] [CrossRef] [PubMed]
  194. Martins, I.J. The global obesity epidemic is related to stroke, dementia and Alzheimer’s disease. JSM Alzheimer’s Dis. Relat. Dement. 2014, 1, 1010–1018. [Google Scholar]
  195. Martins, I.J. Induction of NAFLD with increased risk of obesity and chronic diseases in developed countries. Open J. Endocr. Metab. Dis. 2014, 4, 90–110. [Google Scholar] [CrossRef]
  196. Martins, I.J. Diabetes and organ dysfunction in the developing and developed. World Glob. J. Med. Res. F Dis. 2015, 15, 1–8. [Google Scholar]
  197. Leff, J.W.; Fierer, N. Bacterial communities associated with the surfaces of fresh fruits and vegetables. PLoS ONE 2013, 8, e59310. [Google Scholar] [CrossRef] [PubMed]
  198. Howel, K. Bacterial contamination of bread. Am. J. Public Health 1912, 2, 321–324. [Google Scholar] [CrossRef]
  199. Miura, S.; Hasumi, K.; Endo, A. Inhibition of protein prenylation by patulin. FEBS Lett. 1993, 318, 88–90. [Google Scholar] [CrossRef]
  200. Mohamed, A.; Saavedra, L.; di Pardo, A.; Sipione, S.; Posse de Chaves, E. β-Amyloid inhibits protein prenylation and induces cholesterol sequestration by impairing SREBP-2 cleavage. J. Neurosci. 2012, 32, 6490–6500. [Google Scholar] [CrossRef] [PubMed]
  201. Ostrowski, S.M.; Wilkinson, B.L.; Golde, T.E.; Landreth, G. Statins reduce amyloid-β production through inhibition of protein isoprenylation. J. Biol. Chem. 2007, 282, 26832–26844. [Google Scholar] [CrossRef] [PubMed]
  202. PATULIN: Food Safety Watch 2013. Available online: (accessed on 16 September 2015).
  203. Prabhu, P. Analysis of the mycotoxin patulin in apple juice using the flexar FX-15 UHPLC-UV. Available online: (accessed on 16 September 2015).
  204. Ramsay Tainsh, A. Alcohol and mycotoxins. Alcohol Alcohol. 1988, 23, 180–181. [Google Scholar] [PubMed]
  205. Martins, I.J. Appetite Dysregulation and Obesity in Western Countries; Ebook Project; Jones, E., Ed.; GmbH & Co. KG.: Saarbrucken, Germany, 2013. [Google Scholar]
  206. Swick, R.A. Hepatic metabolism and bioactivation of mycotoxins and plant toxins. J. Anim. Sci. 1984, 58, 1017–1028. [Google Scholar] [PubMed]
  207. Martins, I.J. Increased risk for obesity and diabetes with neurodegeneration in developing countries. J. Mol. Genet. Med. 2013, S1, 1–8. [Google Scholar]
  208. Burgess, J.W.; Neville, T.A.; Rouillard, P.; Harder, Z.; Beanlands, D.S.; Sparks, D.L. Phosphatidylinositol increases HDL-C levels in humans. J. Lipid Res. 2005, 46, 350–355. [Google Scholar] [CrossRef] [PubMed]
  209. Devaraja, S.; Girish, K.S.; Santhosh, M.S.; Hemshekhar, M.; Nayaka, S.C.; Kemparaju, K. Fusaric acid, a mycotoxin, and its influence on blood coagulation and platelet function. Blood Coagul. Fibrinolysis. 2013, 24, 419–423. [Google Scholar] [CrossRef] [PubMed]
  210. Prociuk, M.A.; Edel, A.L.; Richard, M.N.; Gavel, N.T.; Ander, B.P.; Dupasquier, C.M.; Pierce, G.N. Cholesterol-induced stimulation of platelet aggregation is prevented by a hempseed-enriched diet. Can. J. Physiol. Pharmacol. 2008, 86, 153–159. [Google Scholar] [CrossRef] [PubMed]
  211. Min, S.H.; Abrams, C.S. Regulation of platelet plug formation by phosphoinositide metabolism. Arch. Biochem. Biophys. 1984, 228, 299–308. [Google Scholar] [CrossRef] [PubMed]
  212. Graff, G.; Nahas, N.; Nikolopoulou, M.; Natarajan, V.; Schmid, H.H. Possible regulation of phospholipase C activity in human platelets by phosphatidylinositol 4′,5′-bisphosphate. Food Chem. Toxicol. 2013, 57, 11–20. [Google Scholar] [CrossRef]
  213. Zundel, W.; Swiersz, L.M.; Giaccia, A. Caveolin 1-mediated regulation of receptor tyrosine kinase-associated phosphatidylinositol 3-kinase activity by ceramide. Mol. Cell. Biol. 2000, 20, 1507–1514. [Google Scholar] [CrossRef] [PubMed]

Share and Cite

MDPI and ACS Style

Martins, I.J. Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases. Int. J. Mol. Sci. 2015, 16, 29554-29573.

AMA Style

Martins IJ. Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases. International Journal of Molecular Sciences. 2015; 16(12):29554-29573.

Chicago/Turabian Style

Martins, Ian James. 2015. "Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases" International Journal of Molecular Sciences 16, no. 12: 29554-29573.

Article Metrics

Back to TopTop