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Cholesterol and Lipoprotein Metabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2018) | Viewed by 92517

Special Issue Editor

Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49 bus 911, 3000 Leuven, Belgium
Interests: lipoproteins; atherosclerosis; coronary heart disease; familial hypercholesterolemia; low-density lipoprotein (LDL) receptor; heart failure; gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cholesterol is an essential structural component of all animal cell membranes and is critical as a determinant of both membrane structural integrity and fluidity. Inborn errors of cholesterol synthesis, like the Smith–Lemli–Opitz syndrome, cause a broad spectrum of effects. On the other hand, the accumulation of cholesterol in the vascular wall is a cardinal feature of atherosclerosis and had already been demonstrated in 1910 by the German chemist and Nobel Prize winner A. Windaus in studies on human atherosclerotic lesions.

Hypercholesterolemia is a risk factor for atherosclerotic vascular disease but its biological and clinical impact is much broader. In the past year, major advances in pharmacological treatment of hypercholesterolemia were realised. The FOURIER trial, evaluating the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab, met both its primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina or coronary revascularization) and the more rigorous key secondary composite endpoint (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). The cost price of PCSK9 inhibitors remains a major obstacle for broad clinical application. More recently, the REVEAL outcomes study evaluating the cholesterol ester transfer protein (CETP) inhibitor anacetrapib met its primary endpoint, significantly reducing major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization) compared to placebo in patients at risk for cardiac events who are already receiving an effective LDL-C lowering regimen.

In general, a strong linear relationship has been demonstrated between absolute low-density lipoprotein (LDL)-cholesterol reduction (mmol/L) and reduction of the rate of major cardiovascular events (%). In contrast, the high-density lipoprotein (HDL) hypothesis, which states that raising HDL may lead to a decrease in coronary heart disease risk, remains unproven. At present, the scientific field of cholesterol and lipoprotein metabolism remains an inexhaustible source of challenging questions and discovery. This Special Issue will cover recent advances in basic science and clinical translation investigations in these fields.

Prof. Dr. Bart De  Geest
Guest Editor

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Keywords

  • Cholesterol
  • Lipoprotein metabolism
  • Low-density lipoproteins
  • High-density lipoproteins
  • Remnant lipoproteins
  • Apolipoprotein B
  • Apolipoprotein A-I
  • Proprotein convertase subtilisin/kexin type 9 
  • Atherosclerotic vascular disease
  • Cholesterol ester transfer protein
  • Ischemic cardiovascular disease
  • Heart failure

Published Papers (13 papers)

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Editorial

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5 pages, 201 KiB  
Editorial
New Perspectives on Cholesterol and Lipoprotein Metabolism
by Bart De Geest and Mudit Mishra
Int. J. Mol. Sci. 2023, 24(14), 11298; https://doi.org/10.3390/ijms241411298 - 11 Jul 2023
Viewed by 770
Abstract
In animals, cholesterol is an essential component of every cellular membrane and is required for cell membrane integrity [...] Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)

Research

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19 pages, 5096 KiB  
Article
Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice
by Mudit Mishra, Ilayaraja Muthuramu, Joseph Pierre Aboumsallem, Herman Kempen and Bart De Geest
Int. J. Mol. Sci. 2018, 19(11), 3399; https://doi.org/10.3390/ijms19113399 - 30 Oct 2018
Cited by 19 | Viewed by 4168
Abstract
Heart failure with preserved ejection fraction (HFpEF) represents a major unmet therapeutic need. This study investigated whether feeding coconut oil (CC diet) for 26 weeks in female C57BL/6N mice induces HFpEF and evaluated the effect of reconstituted high-density lipoprotein (HDL)Milano (MDCO-216) administration [...] Read more.
Heart failure with preserved ejection fraction (HFpEF) represents a major unmet therapeutic need. This study investigated whether feeding coconut oil (CC diet) for 26 weeks in female C57BL/6N mice induces HFpEF and evaluated the effect of reconstituted high-density lipoprotein (HDL)Milano (MDCO-216) administration on established HFpEF. Eight intraperitoneal injections of MDCO-216 (100 mg/kg protein concentration) or of an equivalent volume of control buffer were executed with a 48-h interval starting at 26 weeks after the initiation of the diet. Feeding the CC diet for 26 weeks induced pathological left ventricular hypertrophy characterized by a 17.1% (p < 0.0001) lower myocardial capillary density and markedly (p < 0.0001) increased interstitial fibrosis compared to standard chow (SC) diet mice. Parameters of systolic and diastolic function were significantly impaired in CC diet mice resulting in a reduced stroke volume, decreased cardiac output, and impaired ventriculo-arterial coupling. However, ejection fraction was preserved. Administration of MDCO-216 in CC diet mice reduced cardiac hypertrophy, increased capillary density (p < 0.01), and reduced interstitial fibrosis (p < 0.01). MDCO-216 treatment completely normalized cardiac function, lowered myocardial acetyl-coenzyme A carboxylase levels, and decreased myocardial transforming growth factor-β1 in CC diet mice. In conclusion, the CC diet induced HFpEF. Reconstituted HDLMilano reversed pathological remodeling and functional cardiac abnormalities. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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17 pages, 2014 KiB  
Article
Novel Insights into Concepts and Directionality of Maternal–Fetal Cholesterol Transfer across the Human Placenta
by Sampada Kallol, Xiao Huang, Stefan Müller, Corneille Edgar Ontsouka and Christiane Albrecht
Int. J. Mol. Sci. 2018, 19(8), 2334; https://doi.org/10.3390/ijms19082334 - 09 Aug 2018
Cited by 24 | Viewed by 4074
Abstract
Cholesterol is indispensable for cellular membrane composition and function. It is also a precursor for the synthesis of steroid hormones, which promote, among others, the maturation of fetal organs. A role of the ATP-binding-cassette-transporter-A1 (ABCA1) in the transport of maternal cholesterol to the [...] Read more.
Cholesterol is indispensable for cellular membrane composition and function. It is also a precursor for the synthesis of steroid hormones, which promote, among others, the maturation of fetal organs. A role of the ATP-binding-cassette-transporter-A1 (ABCA1) in the transport of maternal cholesterol to the fetus was suggested by transferring cholesterol to apolipoprotein-A-1 (apo-A1), but the directionality of the apoA-1/ABCA1-dependent cholesterol transport remains unclear. We isolated primary trophoblasts from term placentae to test the hypotheses that (1) apoA-1/ABCA1 dispatches cholesterol mainly towards the fetus to support fetal developmental maturation at term, and (2) differentiated syncytiotrophoblasts (STB) exert higher cholesterol transport activity than undifferentiated cytotrophoblasts (CTB). As experimental models, we used (1) trophoblast monolayers grown on Transwell® system consisting of apical (maternal-like) and basal (fetal-like) compartments, and (2) trophoblasts grown on conventional culture plates at CTB and STB stages. Surprisingly, apoA-1-mediated cholesterol efflux operated almost exclusively at the apical-maternal side, where ABCA1 was also localized by immunofluorescence. We found greater cholesterol efflux capacity in STB, which was increased by liver-X-receptor agonist treatment and decreased by ABCA1 inhibition. We conclude that at term the apoA-1/ABCA1 pathway is rather involved in cholesterol transport to the mother than in transfer to the fully developed fetus. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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17 pages, 24489 KiB  
Article
Exploring the Roles of CREBRF and TRIM2 in the Regulation of Angiogenesis by High-Density Lipoproteins
by Nathan K. P. Wong, Helena Cheung, Emma L. Solly, Laura Z. Vanags, William Ritchie, Stephen J. Nicholls, Martin K. C. Ng, Christina A. Bursill and Joanne T. M. Tan
Int. J. Mol. Sci. 2018, 19(7), 1903; https://doi.org/10.3390/ijms19071903 - 28 Jun 2018
Cited by 13 | Viewed by 4906
Abstract
Angiogenesis, the process of forming new blood vessels, is crucial in the physiological response to ischemia, though it can be detrimental as part of inflammation and tumorigenesis. We have previously shown that high-density lipoproteins (HDL) modulate angiogenesis in a context-specific manner via distinct [...] Read more.
Angiogenesis, the process of forming new blood vessels, is crucial in the physiological response to ischemia, though it can be detrimental as part of inflammation and tumorigenesis. We have previously shown that high-density lipoproteins (HDL) modulate angiogenesis in a context-specific manner via distinct classical signalling pathways, enhancing hypoxia-induced angiogenesis while suppressing inflammatory-driven angiogenesis. Whether additional novel targets exist to account for these effects are unknown. A microarray approach identified two novel genes, cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor (CREBRF) and tripartite motif-containing protein 2 (TRIM2) that were upregulated by reconstituted HDL (rHDL). We measured CREBRF and TRIM2 expression in human coronary artery endothelial cells following incubation with rHDL and exposure to either hypoxia or an inflammatory stimulus. We found that CREBRF and TRIM2 mRNA were significantly upregulated by rHDL, particularly in response to its phospholipid component 1-palmitoyl-2-linoleoyl-phosphatidylcholine, however, protein expression was not significantly altered. Knockdown of TRIM2 impaired endothelial cell tubulogenesis in vitro in both hypoxia and inflammation, implying a necessary role in angiogenesis. Furthermore, TRIM2 knockdown attenuated rHDL-induced tubule formation in hypoxia, suggesting that it is important in mediating the pro-angiogenic action of rHDL. Our study has implications for understanding the regulation of angiogenesis in both of these pathophysiological contexts by HDL. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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15 pages, 1976 KiB  
Article
Niemann-Pick Type C2 Protein Regulates Free Cholesterol Accumulation and Influences Hepatic Stellate Cell Proliferation and Mitochondrial Respiration Function
by Yuan-Hsi Wang, Yuh-Ching Twu, Chung-Kwe Wang, Fu-Zhen Lin, Chun-Ya Lee and Yi-Jen Liao
Int. J. Mol. Sci. 2018, 19(6), 1678; https://doi.org/10.3390/ijms19061678 - 05 Jun 2018
Cited by 19 | Viewed by 4735
Abstract
Liver fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. A high-cholesterol diet is associated with liver fibrosis via the accumulation of free cholesterol in hepatic stellate cells (HSCs). Niemann-Pick type C2 (NPC2) plays an important role [...] Read more.
Liver fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. A high-cholesterol diet is associated with liver fibrosis via the accumulation of free cholesterol in hepatic stellate cells (HSCs). Niemann-Pick type C2 (NPC2) plays an important role in the regulation of intracellular free cholesterol homeostasis via direct binding with free cholesterol. Previously, we reported that NPC2 was downregulated in liver cirrhosis tissues. Loss of NPC2 enhanced the accumulation of free cholesterol in HSCs and made them more susceptible to transforming growth factor (TGF)-β1. In this study, we showed that knockdown of NPC2 resulted in marked increases in platelet-derived growth factor BB (PDGF-BB)-induced HSC proliferation through enhanced extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinases (JNK), and protein kinase B (AKT) phosphorylation. In contrast, NPC2 overexpression decreased PDGF-BB-induced cell proliferation by inhibiting p38, JNK, and AKT phosphorylation. Although NPC2 expression did not affect caspase-related apoptosis, the autophagy marker light chain 3β (LC3B) was decreased in NPC2 knockdown, and free cholesterol accumulated in the HSCs. The mitochondrial respiration functions (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were decreased in NPC2 knockdown, and free cholesterol accumulated in the HSCs, while NPC2-overexpressed cells remained normal. In addition, NPC2 expression did not affect the susceptibility of HSCs to lipopolysaccharides (LPS), and U18666A treatment induced free cholesterol accumulation, which enhanced LPS-induced Toll-like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 phosphorylation, interleukin (IL)-1 and IL-6 expression. Our study demonstrated that NPC2-mediated free cholesterol homeostasis controls HSC proliferation and mitochondrial function. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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18 pages, 3383 KiB  
Article
Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels
by Chuantao Jiang, Hersharan Nischal, Hua Sun, Li Li, Ying Cao, Peng Wei, Jui-Yoa Chang and Ba-Bie Teng
Int. J. Mol. Sci. 2018, 19(2), 640; https://doi.org/10.3390/ijms19020640 - 24 Feb 2018
Cited by 2 | Viewed by 4288
Abstract
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in [...] Read more.
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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1643 KiB  
Article
Relationship between Lipid Phenotypes, Overweight, Lipid Lowering Drug Response and KIF6 and HMG-CoA Genotypes in a Subset of the Brisighella Heart Study Population
by Sabrina Angelini, Martina Rosticci, Gianmichele Massimo, Muriel Musti, Gloria Ravegnini, Nicola Consolini, Giulia Sammarini, Sergio D’Addato, Elisabetta Rizzoli, Dauren Botbayev, Claudio Borghi, Giorgio Cantelli-Forti, Arrigo F. Cicero and Patrizia Hrelia
Int. J. Mol. Sci. 2018, 19(1), 49; https://doi.org/10.3390/ijms19010049 - 24 Dec 2017
Cited by 7 | Viewed by 3450
Abstract
The existence of genetic traits might explain the susceptibility to develop hypercholesterolemia and the inter-individual differences in statin response. This study was performed to evaluate whether individuals’ polymorphisms in HMG-CoA and KIF6 genes are independently associated with hypercholesterolemia, other lipid-associated traits, and statin [...] Read more.
The existence of genetic traits might explain the susceptibility to develop hypercholesterolemia and the inter-individual differences in statin response. This study was performed to evaluate whether individuals’ polymorphisms in HMG-CoA and KIF6 genes are independently associated with hypercholesterolemia, other lipid-associated traits, and statin response in unselected individuals enrolled in the Brisighella heart study (Survey 2012). A total of 1622 individuals, of which 183 under statin medication, were genotyped for a total of five polymorphisms (KIF6 rs20455, rs9471077, rs9462535; HMG-CoA rs3761740, rs3846662). The relationships between the five loci and clinical characteristics were analyzed. The principal basic parameters calculated on 12 h fasting blood included total cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Low-Density Lipoprotein Cholesterol (LDL-C), and triglycerides (TG). Hypercholesterolemia was defined as a TC >200 mg/dL or use of lipid-lowering medication. 965 individuals were characterized by hypercholesterolemia; these subjects were significantly older (p < 0.001), with body mass index (BMI) and waist circumference significantly higher (p < 0.001) compared to the others. HMG-CoA rs3846662 GG genotype was significantly over-represented in the hypercholesterolemic group (p = 0.030). HMG-CoA rs3846662 genotype was associated with the level of TC and LDL-C. Furthermore, in the same subset of untreated subjects, we observed a significant correlation between the KIF6 rs20455 and HDL-C. KIF6 variants were associated with a significantly lower (rs20455) or higher (rs9471077 and rs9462535) risk of obesity, in males only. No association between responsiveness to statins and the polymorphisms under investigation were observed. Our results showed associations between HMG-CoA rs3846662 and KIF6 rs20455 and lipid phenotypes, which may have an influence on dyslipidemia-related events. Moreover, this represents the first study implicating KIF6 variants with obesity in men, and point to the possible involvement of this genetic locus in the known gender-related differences in coronary artery disease. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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Review

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21 pages, 2482 KiB  
Review
Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease
by Asier Benito-Vicente, Kepa B. Uribe, Shifa Jebari, Unai Galicia-Garcia, Helena Ostolaza and Cesar Martin
Int. J. Mol. Sci. 2018, 19(11), 3426; https://doi.org/10.3390/ijms19113426 - 01 Nov 2018
Cited by 76 | Viewed by 17374
Abstract
Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine [...] Read more.
Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine and, intracellularly synthesized cholesterol that is mainly synthesized in the liver. Once acquired, both are delivered to peripheral tissues in a lipoprotein dependent mechanism. Malfunctioning of cholesterol metabolism is caused by multiple hereditary diseases, including Familial Hypercholesterolemia, Sitosterolemia Type C and Niemann-Pick Type C1. Of these, familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder characterized by high plasma cholesterol levels. Its frequency is estimated to be 1:200 and, if untreated, increases the risk of premature cardiovascular disease. This review aims to summarize the current knowledge on cholesterol metabolism and the relation of FH to cholesterol homeostasis with special focus on the genetics, diagnosis and treatment. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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26 pages, 772 KiB  
Review
Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases
by Thomas Sonnweber, Alex Pizzini, Manfred Nairz, Günter Weiss and Ivan Tancevski
Int. J. Mol. Sci. 2018, 19(11), 3285; https://doi.org/10.3390/ijms19113285 - 23 Oct 2018
Cited by 248 | Viewed by 14232
Abstract
Lipid and immune pathways are crucial in the pathophysiology of metabolic and cardiovascular disease. Arachidonic acid (AA) and its derivatives link nutrient metabolism to immunity and inflammation, thus holding a key role in the emergence and progression of frequent diseases such as obesity, [...] Read more.
Lipid and immune pathways are crucial in the pathophysiology of metabolic and cardiovascular disease. Arachidonic acid (AA) and its derivatives link nutrient metabolism to immunity and inflammation, thus holding a key role in the emergence and progression of frequent diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. We herein present a synopsis of AA metabolism in human health, tissue homeostasis, and immunity, and explore the role of the AA metabolome in diverse pathophysiological conditions and diseases. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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13 pages, 1557 KiB  
Review
Role of Membrane Cholesterol Levels in Activation of Lyn upon Cell Detachment
by Takao Morinaga, Noritaka Yamaguchi, Yuji Nakayama, Masatoshi Tagawa and Naoto Yamaguchi
Int. J. Mol. Sci. 2018, 19(6), 1811; https://doi.org/10.3390/ijms19061811 - 19 Jun 2018
Cited by 6 | Viewed by 5118
Abstract
Cholesterol, a major component of the plasma membrane, determines the physical
properties of biological membranes and plays a critical role in the assembly of membrane
microdomains. Enrichment or deprivation of membrane cholesterol affects the activities of many
signaling molecules at the plasma membrane.
[...] Read more.
Cholesterol, a major component of the plasma membrane, determines the physical
properties of biological membranes and plays a critical role in the assembly of membrane
microdomains. Enrichment or deprivation of membrane cholesterol affects the activities of many
signaling molecules at the plasma membrane. Cell detachment changes the structure of the plasma
membrane and influences the localizations of lipids, including cholesterol. Recent studies showed
that cell detachment changes the activities of a variety of signaling molecules. We previously reported
that the localization and the function of the Src-family kinase Lyn are critically regulated by its
membrane anchorage through lipid modifications. More recently, we found that the localization and
the activity of Lyn were changed upon cell detachment, although the manners of which vary between
cell types. In this review, we highlight the changes in the localization of Lyn and a role of cholesterol
in the regulation of Lyn’s activation following cell detachment.

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(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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13 pages, 953 KiB  
Review
The Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Lipid Metabolism, Glucose Homeostasis and Inflammation
by Virginia Actis Dato and Gustavo Alberto Chiabrando
Int. J. Mol. Sci. 2018, 19(6), 1780; https://doi.org/10.3390/ijms19061780 - 15 Jun 2018
Cited by 72 | Viewed by 7786
Abstract
Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin [...] Read more.
Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin resistance, dyslipidemia, and central obesity. The low-density lipoprotein receptor-related protein 1 (LRP1—A member of the LDL receptor family) is an endocytic and signaling receptor that is expressed in several tissues. It is involved in the clearance of chylomicron remnants from circulation, and has been demonstrated to play a key role in the lipid metabolism at the hepatic level. Recent studies have shown that LRP1 is involved in insulin receptor (IR) trafficking and intracellular signaling activity, which have an impact on the regulation of glucose homeostasis in adipocytes, muscle cells, and brain. In addition, LRP1 has the potential to inhibit or sustain inflammation in macrophages, depending on its cellular expression, as well as the presence of particular types of ligands in the extracellular microenvironment. In this review, we summarize existing perspectives and the latest innovations concerning the role of tissue-specific LRP1 in lipoprotein and glucose metabolism, and examine its ability to mediate inflammatory processes related to MetS and atherosclerosis. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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21 pages, 1833 KiB  
Review
The Role of High-Density Lipoproteins in Diabetes and Its Vascular Complications
by Nathan K. P. Wong, Stephen J. Nicholls, Joanne T. M. Tan and Christina A. Bursill
Int. J. Mol. Sci. 2018, 19(6), 1680; https://doi.org/10.3390/ijms19061680 - 05 Jun 2018
Cited by 41 | Viewed by 7692
Abstract
Almost 600 million people are predicted to have diabetes mellitus (DM) by 2035. Diabetic patients suffer from increased rates of microvascular and macrovascular complications, associated with dyslipidaemia, impaired angiogenic responses to ischaemia, accelerated atherosclerosis, and inflammation. Despite recent treatment advances, many diabetic patients [...] Read more.
Almost 600 million people are predicted to have diabetes mellitus (DM) by 2035. Diabetic patients suffer from increased rates of microvascular and macrovascular complications, associated with dyslipidaemia, impaired angiogenic responses to ischaemia, accelerated atherosclerosis, and inflammation. Despite recent treatment advances, many diabetic patients remain refractory to current approaches, highlighting the need for alternative agents. There is emerging evidence that high-density lipoproteins (HDL) are able to rescue diabetes-related vascular complications through diverse mechanisms. Such protective functions of HDL, however, can be rendered dysfunctional within the pathological milieu of DM, triggering the development of vascular complications. HDL-modifying therapies remain controversial as many have had limited benefits on cardiovascular risk, although more recent trials are showing promise. This review will discuss the latest data from epidemiological, clinical, and pre-clinical studies demonstrating various roles for HDL in diabetes and its vascular complications that have the potential to facilitate its successful translation. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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18 pages, 1454 KiB  
Review
Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia: A Retrospective on Functional Characterization of LDLr Variants
by Asier Benito-Vicente, Kepa B. Uribe, Shifa Jebari, Unai Galicia-Garcia, Helena Ostolaza and Cesar Martin
Int. J. Mol. Sci. 2018, 19(6), 1676; https://doi.org/10.3390/ijms19061676 - 05 Jun 2018
Cited by 36 | Viewed by 12958
Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr). With a prevalence as high as 1/200 in some populations, genetic screening for pathogenic LDLr mutations is a cost-effective approach [...] Read more.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr). With a prevalence as high as 1/200 in some populations, genetic screening for pathogenic LDLr mutations is a cost-effective approach in families classified as ‘definite’ or ‘probable’ FH and can help to early diagnosis. However, with over 2000 LDLr variants identified, distinguishing pathogenic mutations from benign mutations is a long-standing challenge in the field. In 1998, the World Health Organization (WHO) highlighted the importance of improving the diagnosis and prognosis of FH patients thus, identifying LDLr pathogenic variants is a longstanding challenge to provide an accurate genetic diagnosis and personalized treatments. In recent years, accessible methodologies have been developed to assess LDLr activity in vitro, providing experimental reproducibility between laboratories all over the world that ensures rigorous analysis of all functional studies. In this review we present a broad spectrum of functionally characterized missense LDLr variants identified in patients with FH, which is mandatory for a definite diagnosis of FH. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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