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Special Issue "Emerging Role of Lipids in Metabolism and Disease"

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

Deadline for manuscript submissions: 25 April 2020.

Special Issue Editors

Prof. Dr. Valentina Pallottini
E-Mail Website
Guest Editor
Department of Science, University Roma Tre, Viale Marconi, 446, Rome
Interests: Cholesterol metabolism; HMG-CoA reductase; neurodegeneration; neurodevelopmental diseases
Dr. Marco Segatto
E-Mail Website
Guest Editor
University of Molise, Rome, Italy
Interests: lipid metabolism; muscle metabolism; neurotrophins; neurodegeneration; epigenetic regulation; inflammation

Special Issue Information

Dear Colleagues,

Although initially regarded as a passive method of energy storage, lipids are now considered molecules with pivotal structural and functional roles. Notably, they serve as integral components of cellular membranes and act as crucial messengers in the regulation of cell homeostasis. In recent years, the role of lipids in homeostasis maintenance, derived from both nutrition and endogenous biosynthesis, attracted the interest of several researchers because of its involvement in human health. Lipid disorders are at the root of several diseases characterized by altered lipid metabolism in different tissues. Metabolic syndrome and cardiovascular disease, for instance, are closely related to these metabolic dysfunctions. Moreover, connections with misbalances of cholesterol homeostasis in neurodegenerative and neurodevelopmental disorders have also been demonstrated. Thus, the aim of this Special Issue is to gather research papers focused on this topic and, therefore, bring to the forefront new insights into physiopathological aspects of lipid disorders. Papers from different experts in the field will provide an interdisciplinary approach that will identify how the manipulation of lipid metabolism can represent a very attractive target for designing novel therapeutic targets to counteract several pathologies.

Prof. Dr. Valentina Pallottini
Dr. Marco Segatto
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cholesterol
  • Fatty acids
  • Lipoproteins
  • Lipids
  • Metabolism
  • Metabolic diseases
  • Neurodegeneration and lipids
  • Neurodevelopment and lipids
  • Lipid signaling
  • Lipids and inflammation
  • Lipids in cancer
  • Cardiovascular diseases
  • Lipid rafts
  • Post-translational lipid modifications
  • Polyunsaturated fatty acids
  • Cannabinoids
  • Eicosanoids

Published Papers (6 papers)

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Research

Open AccessArticle
Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis
Int. J. Mol. Sci. 2020, 21(4), 1297; https://doi.org/10.3390/ijms21041297 (registering DOI) - 14 Feb 2020
Abstract
The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the [...] Read more.
The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)
Open AccessArticle
High-Cholesterol Diet Decreases the Level of Phosphatidylinositol 4,5-Bisphosphate by Enhancing the Expression of Phospholipase C (PLCβ1) in Rat Brain
Int. J. Mol. Sci. 2020, 21(3), 1161; https://doi.org/10.3390/ijms21031161 - 10 Feb 2020
Abstract
Cholesterol is a critical component of eukaryotic membranes, where it contributes to regulating transmembrane signaling, cell–cell interaction, and ion transport. Dysregulation of cholesterol levels in the brain may induce neurodegenerative diseases, such as Alzheimer’s disease, Parkinson disease, and Huntington disease. We previously reported [...] Read more.
Cholesterol is a critical component of eukaryotic membranes, where it contributes to regulating transmembrane signaling, cell–cell interaction, and ion transport. Dysregulation of cholesterol levels in the brain may induce neurodegenerative diseases, such as Alzheimer’s disease, Parkinson disease, and Huntington disease. We previously reported that augmenting membrane cholesterol level regulates ion channels by decreasing the level of phosphatidylinositol 4,5-bisphosphate (PIP2), which is closely related to β-amyloid (Aβ) production. In addition, cholesterol enrichment decreased PIP2 levels by increasing the expression of the β1 isoform of phospholipase C (PLC) in cultured cells. In this study, we examined the effect of a high-cholesterol diet on phospholipase C (PLCβ1) expression and PIP2 levels in rat brain. PIP2 levels were decreased in the cerebral cortex in rats on a high-cholesterol diet. Levels of PLCβ1 expression correlated with PIP2 levels. However, cholesterol and PIP2 levels were not correlated, suggesting that PIP2 level is regulated by cholesterol via PLCβ1 expression in the brain. Thus, there exists cross talk between cholesterol and PIP2 that could contribute to the pathogenesis of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)
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Open AccessArticle
Adipose Tissue and Brain Metabolic Responses to Western Diet—Is There a Similarity between the Two?
Int. J. Mol. Sci. 2020, 21(3), 786; https://doi.org/10.3390/ijms21030786 - 25 Jan 2020
Abstract
Dietary fats and sugars were identified as risk factors for overweight and neurodegeneration, especially in middle-age, an earlier stage of the aging process. Therefore, our aim was to study the metabolic response of both white adipose tissue and brain in middle aged rats [...] Read more.
Dietary fats and sugars were identified as risk factors for overweight and neurodegeneration, especially in middle-age, an earlier stage of the aging process. Therefore, our aim was to study the metabolic response of both white adipose tissue and brain in middle aged rats fed a typical Western diet (high in saturated fats and fructose, HFF) and verify whether a similarity exists between the two tissues. Specific cyto/adipokines (tumor necrosis factor alpha (TNF-α), adiponectin), critical obesity-inflammatory markers (haptoglobin, lipocalin), and insulin signaling or survival protein network (insulin receptor substrate 1 (IRS), Akt, Erk) were quantified in epididymal white adipose tissue (e-WAT), hippocampus, and frontal cortex. We found a significant increase of TNF-α in both e-WAT and hippocampus of HFF rats, while the expression of haptoglobin and lipocalin was differently affected in the various tissues. Interestingly, adiponectin amount was found significantly reduced in e-WAT, hippocampus, and frontal cortex of HFF rats. Insulin signaling was impaired by HFF diet in e-WAT but not in brain. The above changes were associated with the decrease in brain derived neurotrophic factor (BDNF) and synaptotagmin I and the increase in post-synaptic protein PSD-95 in HFF rats. Overall, our investigation supports for the first time similarities in the response of adipose tissue and brain to Western diet. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)
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Open AccessArticle
Circulating CRP Levels Are Associated with Epicardial and Visceral Fat Depots in Women with Metabolic Syndrome Criteria
Int. J. Mol. Sci. 2019, 20(23), 5981; https://doi.org/10.3390/ijms20235981 - 27 Nov 2019
Abstract
Sexual dimorphism accounts for significant differences in adipose tissue mass and distribution. However, how the crosstalk between visceral and ectopic fat depots occurs and which are the determinants of ectopic fat expansion and dysfunction remains unknown. Here, we focused on the impact of [...] Read more.
Sexual dimorphism accounts for significant differences in adipose tissue mass and distribution. However, how the crosstalk between visceral and ectopic fat depots occurs and which are the determinants of ectopic fat expansion and dysfunction remains unknown. Here, we focused on the impact of gender in the crosstalk between visceral and epicardial fat depots and the role of adipocytokines and high-sensitivity C-reactive protein (hs-CRP). A total of 141 outward patients (both men and women) with one or more defining criteria for metabolic syndrome (MetS) were consecutively enrolled. For all patients, demographic and clinical data were collected and ultrasound assessment of visceral adipose tissue (VFth) and epicardial fat (EFth) thickness was performed. Hs-CRP and adipocytokine levels were assessed by enzyme-linked immunosorbent assay (ELISA). Men were characterized by increased VFth and EFth (p-value < 0.001 and 0.014, respectively), whereas women showed higher levels of adiponectin and leptin (p-value < 0.001 for both). However, only in women VFth and EFth significantly correlated between them (p = 0.013) and also with leptin (p < 0.001 for both) and hs-CRP (p = 0.005 and p = 0.028, respectively). Linear regression confirmed an independent association of both leptin and hs-CRP with VFth in women, also after adjustment for age and MetS (p = 0.012 and 0.007, respectively). In conclusion, men and women present differences in epicardial fat deposition and systemic inflammation. An intriguing association between visceral/epicardial fat depots and chronic low-grade inflammation also emerged. In women Although a further validation in larger studies is needed, these findings suggest a critical role of sex in stratification of obese/dysmetabolic patients. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)
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Open AccessArticle
Epinephrine Infiltration of Adipose Tissue Impacts MCF7 Breast Cancer Cells and Total Lipid Content
Int. J. Mol. Sci. 2019, 20(22), 5626; https://doi.org/10.3390/ijms20225626 - 11 Nov 2019
Abstract
Background: Considering the positive or negative potential effects of adipocytes, depending on their lipid composition, on breast tumor progression, it is important to evaluate whether adipose tissue (AT) harvesting procedures, including epinephrine infiltration, may influence breast cancer progression. Methods: Culture medium conditioned with [...] Read more.
Background: Considering the positive or negative potential effects of adipocytes, depending on their lipid composition, on breast tumor progression, it is important to evaluate whether adipose tissue (AT) harvesting procedures, including epinephrine infiltration, may influence breast cancer progression. Methods: Culture medium conditioned with epinephrine-infiltrated adipose tissue was tested on human Michigan Cancer Foundation-7 (MCF7) breast cancer cells, cultured in monolayer or in oncospheres. Lipid composition was evaluated depending on epinephrine-infiltration for five patients. Epinephrine-infiltrated adipose tissue (EI-AT) or corresponding conditioned medium (EI-CM) were injected into orthotopic breast carcinoma induced in athymic mouse. Results: EI-CM significantly increased the proliferation rate of MCF7 cells Moreover EI-CM induced an output of the quiescent state of MCF7 cells, but it could be either an activator or inhibitor of the epithelial mesenchymal transition as indicated by gene expression changes. EI-CM presented a significantly higher lipid total weight compared with the conditioned medium obtained from non-infiltrated-AT of paired-patients. In vivo, neither the EI-CM or EI-AT injection significantly promoted MCF7-induced tumor growth. Conclusions: Even though conditioned media are widely used to mimic the secretome of cells or tissues, they may produce different effects on tumor progression, which may explain some of the discrepancy observed between in vitro, preclinical and clinical data using AT samples. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)
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Open AccessArticle
Neutral Sphingomyelinase Modulation in the Protective/Preventive Role of rMnSOD from Radiation-Induced Damage in the Brain
Int. J. Mol. Sci. 2019, 20(21), 5431; https://doi.org/10.3390/ijms20215431 - 31 Oct 2019
Abstract
Studies on the relationship between reactive oxygen species (ROS)/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that [...] Read more.
Studies on the relationship between reactive oxygen species (ROS)/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that ROS modulate the activation of SMase. The human recombinant manganese superoxide dismutase (rMnSOD) exerting a radioprotective effect on normal cells, qualifies as a possible pharmaceutical tool to prevent and/or cure damages derived from accidental exposure to ionizing radiation. This study aimed to identify neutral SMase (nSMase) as novel molecule connecting rMnSOD to its radiation protective effects. We used a new, and to this date, unique, experimental model to assess the effect of both radiation and rMnSOD in the brain of mice, within a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia). Mice were exposed to a set of minor γ radiation and neutrons and a spectrum of neutrons, simulating the radiation levels to which cosmonauts will be exposed during deep-space, long-term missions. Groups of mice were treated or not-treated (controls) with daily subcutaneous injections of rMnSOD during a period of 10 days. An additional group of mice was also pretreated with rMnSOD for three days before irradiation, as a model for preventive measures. We demonstrate that rMnSOD significantly protects the midbrain cells from radiation-induced damage, inducing a strong upregulation of nSMase gene and protein expression. Pretreatment with rMnSOD before irradiation protects the brain with a value of very high nSMase activity, indicating that high levels of activity might be sufficient to exert the rMnSOD preventive role. In conclusion, the protective effect of rMnSOD from radiation-induced brain damage may require nSMase enzyme. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Lipids and lipid-processing pathways in drug delivery and therapeutics 
 
Milica Markovic, Shimon Ben-Shabat, Aaron Aponick, Ellen M. Zimmermann, and Arik Dahan.
 
The aim of this work is to provide an overview of the relevant endogenous lipid processing pathways, mainly in the context of drug absorption, followed by drug delivery/therapeutic use of lipids and lipid-drug conjugates. Lipids can be biomarkers of some pathological processes, and can also have endogenous therapeutic effects for certain diseases. Various lipids (fatty acids, triglycerides, phospholipids, and steroids), their role in physiological processes and in disease state, their physiological barriers, current uses and possible clinical benefits are presented. By conjugating these lipids to a drug moiety, numerous potential benefits can be accomplished, one being the enhanced treatment effect, due to joint effects of the lipid carrier and the drug moiety. In addition, lipid-drug conjugates have enlarged lipophilicity comparing to the parent drug, and can hence meaningfully improve the drug pharmacokinetic profile and bioavailability, join the natural lipid pathways and thus achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable passing the barriers in the body. Furthermore, the role of lipases in drug release is described in brief. Altogether, new mechanisms of the lipid role in diseases are constantly revealed, and novel ways to exploit these mechanisms for the optimal drug design that would improve different drug
delivery/therapy aspects are continuously emerging.
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