International Journal of Molecular Sciences

Editorial

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5 pages, 184 KiB

Open AccessEditorial

Facts about Fats: New Insights into the Role of Lipids in Metabolism, Disease and Therapy

by Marco Segatto and Valentina Pallottini

Int. J. Mol. Sci. 2020, 21(18), 6651; https://doi.org/10.3390/ijms21186651 - 11 Sep 2020

Cited by 8 | Viewed by 2657

Abstract

Although initially regarded as a passive system to store energy, lipids are now considered to play crucial, structural and functional roles in almost all the biological processes involved in the regulation of physiological and pathological conditions [...] Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

Research

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11 pages, 1490 KiB

Open AccessArticle

Acid and Neutral Sphingomyelinase Behavior in Radiation-Induced Liver Pyroptosis and in the Protective/Preventive Role of rMnSOD

by Samuela Cataldi, Antonella Borrelli, Maria Rachele Ceccarini, Irina Nakashidze, Michela Codini, Oleg Belov, Alexander Ivanov, Eugene Krasavin, Ivana Ferri, Carmela Conte, Federica Filomena Patria, Tommaso Beccari, Aldo Mancini, Francesco Curcio, Francesco Saverio Ambesi-Impiombato and Elisabetta Albi

Int. J. Mol. Sci. 2020, 21(9), 3281; https://doi.org/10.3390/ijms21093281 - 6 May 2020

Cited by 15 | Viewed by 3625

Abstract

Sphingomyelins (SMs) are a class of relevant bioactive molecules that act as key modulators of different cellular processes, such as growth arrest, exosome formation, and the inflammatory response influenced by many environmental conditions, leading to pyroptosis, a form of programmed cell death due [...] Read more.

Sphingomyelins (SMs) are a class of relevant bioactive molecules that act as key modulators of different cellular processes, such as growth arrest, exosome formation, and the inflammatory response influenced by many environmental conditions, leading to pyroptosis, a form of programmed cell death due to Caspase-1 involvement. To study liver pyroptosis and hepatic SM metabolism via both lysosomal acid SMase (aSMase) and endoplasmic reticulum/nucleus neutral SMase (nSMase) during the exposure of mice to radiation and to ascertain if this process can be modulated by protective molecules, we used an experimental design (previously used by us) to evaluate the effects of both ionizing radiation and a specific protective molecule (rMnSOD) in the brain in collaboration with the Joint Institute for Nuclear Research, Dubna (Russia). As shown by the Caspase-1 immunostaining of the liver sections, the radiation resulted in the loss of the normal cell structure alongside a progressive and dose-dependent increase of the labelling, treatment, and pretreatment with rMnSOD, which had a significant protective effect on the livers. SM metabolic analyses, performed on aSMase and nSMase gene expression, as well as protein content and activity, proved that rMnSOD was able to significantly reduce radiation-induced damage by playing both a protective role via aSMase and a preventive role via nSMase. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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16 pages, 4306 KiB

Open AccessArticle

Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

by Claudia Tonini, Mayra Colardo, Barbara Colella, Sabrina Di Bartolomeo, Francesco Berardinelli, Giuseppina Caretti, Valentina Pallottini and Marco Segatto

Int. J. Mol. Sci. 2020, 21(4), 1297; https://doi.org/10.3390/ijms21041297 - 14 Feb 2020

Cited by 30 | Viewed by 5024

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)

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10 pages, 1643 KiB

Open AccessArticle

High-Cholesterol Diet Decreases the Level of Phosphatidylinositol 4,5-Bisphosphate by Enhancing the Expression of Phospholipase C (PLCβ1) in Rat Brain

by Yoon Sun Chun and Sungkwon Chung

Int. J. Mol. Sci. 2020, 21(3), 1161; https://doi.org/10.3390/ijms21031161 - 10 Feb 2020

Cited by 7 | Viewed by 3059

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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19 pages, 5972 KiB

Open AccessArticle

Adipose Tissue and Brain Metabolic Responses to Western Diet—Is There a Similarity between the Two?

by Arianna Mazzoli, Maria Stefania Spagnuolo, Cristina Gatto, Martina Nazzaro, Rosa Cancelliere, Raffaella Crescenzo, Susanna Iossa and Luisa Cigliano

Int. J. Mol. Sci. 2020, 21(3), 786; https://doi.org/10.3390/ijms21030786 - 25 Jan 2020

Cited by 19 | Viewed by 4490

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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13 pages, 798 KiB

Open AccessArticle

Circulating CRP Levels Are Associated with Epicardial and Visceral Fat Depots in Women with Metabolic Syndrome Criteria

by Federico Carbone, Maria Stefania Lattanzio, Silvia Minetti, Anna Maria Ansaldo, Daniele Ferrara, Emilio Molina-Molina, Anna Belfiore, Edoardo Elia, Stefania Pugliese, Vincenzo Ostilio Palmieri, Fabrizio Montecucco and Piero Portincasa

Int. J. Mol. Sci. 2019, 20(23), 5981; https://doi.org/10.3390/ijms20235981 - 27 Nov 2019

Cited by 12 | Viewed by 3357

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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15 pages, 2712 KiB

Open AccessArticle

Epinephrine Infiltration of Adipose Tissue Impacts MCF7 Breast Cancer Cells and Total Lipid Content

by Pierre Avril, Luciano Vidal, Sophie Barille-Nion, Louis-Romée Le Nail, Françoise Redini, Pierre Layrolle, Michelle Pinault, Stéphane Chevalier, Pierre Perrot and Valérie Trichet

Int. J. Mol. Sci. 2019, 20(22), 5626; https://doi.org/10.3390/ijms20225626 - 11 Nov 2019

Cited by 7 | Viewed by 3108

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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10 pages, 1284 KiB

Open AccessArticle

Neutral Sphingomyelinase Modulation in the Protective/Preventive Role of rMnSOD from Radiation-Induced Damage in the Brain

by Samuela Cataldi, Antonella Borrelli, Maria Rachele Ceccarini, Irina Nakashidze, Michela Codini, Oleg Belov, Alexander Ivanov, Eugene Krasavin, Ivana Ferri, Carmela Conte, Federica Filomena Patria, Giovanna Traina, Tommaso Beccari, Aldo Mancini, Francesco Curcio, Francesco Saverio Ambesi-Impiombato and Elisabetta Albi

Int. J. Mol. Sci. 2019, 20(21), 5431; https://doi.org/10.3390/ijms20215431 - 31 Oct 2019

Cited by 7 | Viewed by 2969

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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Review

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33 pages, 2232 KiB

Open AccessReview

Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases

by Anna Kloska, Magdalena Węsierska, Marcelina Malinowska, Magdalena Gabig-Cimińska and Joanna Jakóbkiewicz-Banecka

Int. J. Mol. Sci. 2020, 21(17), 6113; https://doi.org/10.3390/ijms21176113 - 25 Aug 2020

Cited by 50 | Viewed by 10323

Abstract

This review discusses how lipophagy and cytosolic lipolysis degrade cellular lipids, as well as how these pathway ys communicate, how they affect lipid metabolism and energy homeostasis in cells and how their dysfunction affects the pathogenesis of lipid storage and lipid metabolism diseases. [...] Read more.

This review discusses how lipophagy and cytosolic lipolysis degrade cellular lipids, as well as how these pathway ys communicate, how they affect lipid metabolism and energy homeostasis in cells and how their dysfunction affects the pathogenesis of lipid storage and lipid metabolism diseases. Answers to these questions will likely uncover novel strategies for the treatment of aforementioned human diseases, but, above all, will avoid destructive effects of high concentrations of lipids—referred to as lipotoxicity—resulting in cellular dysfunction and cell death. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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23 pages, 994 KiB

Open AccessReview

Modulation of DNA Damage Response by Sphingolipid Signaling: An Interplay that Shapes Cell Fate

by Marina Francis, Alaa Abou Daher, Patrick Azzam, Manal Mroueh and Youssef H. Zeidan

Int. J. Mol. Sci. 2020, 21(12), 4481; https://doi.org/10.3390/ijms21124481 - 24 Jun 2020

Cited by 11 | Viewed by 4784

Abstract

Although once considered as structural components of eukaryotic biological membranes, research in the past few decades hints at a major role of bioactive sphingolipids in mediating an array of physiological processes including cell survival, proliferation, inflammation, senescence, and death. A large body of [...] Read more.

Although once considered as structural components of eukaryotic biological membranes, research in the past few decades hints at a major role of bioactive sphingolipids in mediating an array of physiological processes including cell survival, proliferation, inflammation, senescence, and death. A large body of evidence points to a fundamental role for the sphingolipid metabolic pathway in modulating the DNA damage response (DDR). The interplay between these two elements of cell signaling determines cell fate when cells are exposed to metabolic stress or ionizing radiation among other genotoxic agents. In this review, we aim to dissect the mediators of the DDR and how these interact with the different sphingolipid metabolites to mount various cellular responses. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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46 pages, 3825 KiB

Open AccessReview

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

by Vidyani Suryadevara, Ramaswamy Ramchandran, David W. Kamp and Viswanathan Natarajan

Int. J. Mol. Sci. 2020, 21(12), 4257; https://doi.org/10.3390/ijms21124257 - 15 Jun 2020

Cited by 82 | Viewed by 11062

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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21 pages, 2325 KiB

Open AccessReview

The Role of High-Density Lipoproteins in Endothelial Cell Metabolism and Diabetes-Impaired Angiogenesis

by Khalia R. Primer, Peter J. Psaltis, Joanne T.M. Tan and Christina A. Bursill

Int. J. Mol. Sci. 2020, 21(10), 3633; https://doi.org/10.3390/ijms21103633 - 21 May 2020

Cited by 22 | Viewed by 5304

Abstract

Diabetes mellitus affects millions of people worldwide and is associated with devastating vascular complications. A number of these complications, such as impaired wound healing and poor coronary collateral circulation, are characterised by impaired ischaemia-driven angiogenesis. There is increasing evidence that high-density lipoproteins (HDL) [...] Read more.

Diabetes mellitus affects millions of people worldwide and is associated with devastating vascular complications. A number of these complications, such as impaired wound healing and poor coronary collateral circulation, are characterised by impaired ischaemia-driven angiogenesis. There is increasing evidence that high-density lipoproteins (HDL) can rescue diabetes-impaired angiogenesis through a number of mechanisms, including the modulation of endothelial cell metabolic reprogramming. Endothelial cell metabolic reprogramming in response to tissue ischaemia is a driver of angiogenesis and is dysregulated by diabetes. Specifically, diabetes impairs pathways that allow endothelial cells to upregulate glycolysis in response to hypoxia adequately and impairs suppression of mitochondrial respiration. HDL rescues the impairment of the central hypoxia signalling pathway, which regulates these metabolic changes, and this may underpin several of its known pro-angiogenic effects. This review discusses the current understanding of endothelial cell metabolism and how diabetes leads to its dysregulation whilst examining the various positive effects of HDL on endothelial cell function. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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26 pages, 2576 KiB

Open AccessReview

Lipids and Lipid Mediators Associated with the Risk and Pathology of Ischemic Stroke

by Anna Kloska, Marcelina Malinowska, Magdalena Gabig-Cimińska and Joanna Jakóbkiewicz-Banecka

Int. J. Mol. Sci. 2020, 21(10), 3618; https://doi.org/10.3390/ijms21103618 - 20 May 2020

Cited by 47 | Viewed by 7293

Abstract

Stroke is a severe neurological disorder in humans that results from an interruption of the blood supply to the brain. Worldwide, stoke affects over 100 million people each year and is the second largest contributor to disability. Dyslipidemia is a modifiable risk factor [...] Read more.

Stroke is a severe neurological disorder in humans that results from an interruption of the blood supply to the brain. Worldwide, stoke affects over 100 million people each year and is the second largest contributor to disability. Dyslipidemia is a modifiable risk factor for stroke that is associated with an increased risk of the disease. Traditional and non-traditional lipid measures are proposed as biomarkers for the better detection of subclinical disease. In the central nervous system, lipids and lipid mediators are essential to sustain the normal brain tissue structure and function. Pathways leading to post-stroke brain deterioration include the metabolism of polyunsaturated fatty acids. A variety of lipid mediators are generated from fatty acids and these molecules may have either neuroprotective or neurodegenerative effects on the post-stroke brain tissue; therefore, they largely contribute to the outcome and recovery from stroke. In this review, we provide an overview of serum lipids associated with the risk of ischemic stroke. We also discuss the role of lipid mediators, with particular emphasis on eicosanoids, in the pathology of ischemic stroke. Finally, we summarize the latest research on potential targets in lipid metabolic pathways for ischemic stroke treatment and on the development of new stroke risk biomarkers for use in clinical practice. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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14 pages, 604 KiB

Open AccessReview

In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

by Anastasia V. Poznyak, Andrey V. Grechko, Reinhard Wetzker and Alexander N. Orekhov

Int. J. Mol. Sci. 2020, 21(6), 2097; https://doi.org/10.3390/ijms21062097 - 18 Mar 2020

Cited by 17 | Viewed by 5520

Abstract

Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to [...] Read more.

Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr^−/−), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE^−/−) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr^−/− mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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13 pages, 714 KiB

Open AccessReview

The Diabetes Mellitus–Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation

by Anastasia Poznyak, Andrey V. Grechko, Paolo Poggio, Veronika A. Myasoedova, Valentina Alfieri and Alexander N. Orekhov

Int. J. Mol. Sci. 2020, 21(5), 1835; https://doi.org/10.3390/ijms21051835 - 6 Mar 2020

Cited by 588 | Viewed by 43182

Abstract

Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities [...] Read more.

Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities in proteins, lipids, and carbohydrates. Atherosclerosis develops as a result of a multistep process ultimately leading to cardiovascular disease associated with high morbidity and mortality. Alteration of lipid metabolism is a risk factor and characteristic feature of atherosclerosis. Possible links between the two chronic disorders depending on altered metabolic pathways have been investigated in numerous studies. It was shown that both types of diabetes mellitus can actually induce atherosclerosis development or further accelerate its progression. Elevated glucose level, dyslipidemia, and other metabolic alterations that accompany the disease development are tightly involved in the pathogenesis of atherosclerosis at almost every step of the atherogenic process. Chronic inflammation is currently considered as one of the key factors in atherosclerosis development and is present starting from the earliest stages of the pathology initiation. It may also be regarded as one of the possible links between atherosclerosis and diabetes mellitus. However, the data available so far do not allow for developing effective anti-inflammatory therapeutic strategies that would stop atherosclerotic lesion progression or induce lesion reduction. In this review, we summarize the main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship with chronic inflammation. We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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Other

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15 pages, 2882 KiB

Open AccessConcept Paper

Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics

by Milica Markovic, Shimon Ben-Shabat, Aaron Aponick, Ellen M. Zimmermann and Arik Dahan

Int. J. Mol. Sci. 2020, 21(9), 3248; https://doi.org/10.3390/ijms21093248 - 4 May 2020

Cited by 54 | Viewed by 10067

Abstract

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they [...] Read more.

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease)

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