Inhibition of Fatty Acid Translocase (FAT/CD36) Palmitoylation Enhances Hepatic Fatty Acid β-Oxidation by Increasing Its Localization to Mitochondria and Interaction with Long-Chain Acyl-CoA Synthetase 1
“…Both models, NAS and DIS, also showed significant upregulation of PPAR γ expression. Previous studies have also demonstrated an increase in liver PPAR γ expression in NAS model [ 13 , 49 , 50 ]. This may indicate a possible steatogenic role of PPAR γ in the liver in triglyceride accumulation and lipid droplet formation in both models of fatty liver [ 51 , 52 ].…”
(1) Background: With the aging of the population and polypharmacy encountered in the elderly, drug-induced steatosis (DIS) has become frequent cause of non-alcoholic steatosis (NAS). Indeed, NAS and DIS may co-exist, making the ability to distinguish between the entities ever more important. The aim of our study was to study cell culture models of NAS and DIS and determine the effects of liraglutide (LIRA) in those models. (2) Methods: Huh7 cells were treated with oleic acid (OA), or amiodarone (AMD) to establish models of NAS and DIS, respectively. Cells were treated with LIRA and cell viability was assessed by MTT, lipid accumulation by Oil-Red-O staining and triglyceride assay, and intracellular signals involved in hepatosteatosis were quantitated by RT-PCR. (3) Results: After exposure to various OA and AMD concentrations, those that achieved 80% of cells viabilities were used in further experiments to establish NAS and DIS models using 0.5 mM OA and 20 µM AMD, respectively. In both models, LIRA increased cell viability (p < 0.01). Lipid accumulation was increased in both models, with microsteatotic pattern in DIS, and macrosteatotic pattern in NAS which corresponds to greater triglyceride accumulation in latter. LIRA ameliorated these changes (p < 0.001), and downregulated expression of lipogenic ACSL1, PPARγ, and SREBP-1c pathways in the liver (p < 0.01) (4) Conclusions: LIRA ameliorates hepatocyte steatosis in Huh7 cell culture models of NAS and DIS.
“…Both models, NAS and DIS, also showed significant upregulation of PPAR γ expression. Previous studies have also demonstrated an increase in liver PPAR γ expression in NAS model [ 13 , 49 , 50 ]. This may indicate a possible steatogenic role of PPAR γ in the liver in triglyceride accumulation and lipid droplet formation in both models of fatty liver [ 51 , 52 ].…”
(1) Background: With the aging of the population and polypharmacy encountered in the elderly, drug-induced steatosis (DIS) has become frequent cause of non-alcoholic steatosis (NAS). Indeed, NAS and DIS may co-exist, making the ability to distinguish between the entities ever more important. The aim of our study was to study cell culture models of NAS and DIS and determine the effects of liraglutide (LIRA) in those models. (2) Methods: Huh7 cells were treated with oleic acid (OA), or amiodarone (AMD) to establish models of NAS and DIS, respectively. Cells were treated with LIRA and cell viability was assessed by MTT, lipid accumulation by Oil-Red-O staining and triglyceride assay, and intracellular signals involved in hepatosteatosis were quantitated by RT-PCR. (3) Results: After exposure to various OA and AMD concentrations, those that achieved 80% of cells viabilities were used in further experiments to establish NAS and DIS models using 0.5 mM OA and 20 µM AMD, respectively. In both models, LIRA increased cell viability (p < 0.01). Lipid accumulation was increased in both models, with microsteatotic pattern in DIS, and macrosteatotic pattern in NAS which corresponds to greater triglyceride accumulation in latter. LIRA ameliorated these changes (p < 0.001), and downregulated expression of lipogenic ACSL1, PPARγ, and SREBP-1c pathways in the liver (p < 0.01) (4) Conclusions: LIRA ameliorates hepatocyte steatosis in Huh7 cell culture models of NAS and DIS.
“…In the course of NAFLD, fatty acid oxidation is abnormal with the accumulation and saturation of lipids in liver cells. Zeng et al, found that fatty acid translocase (FAT/CD36) on the mitochondrial membrane was heavily palmitoylated in NAFLD, which reduced its ability to transfer long-chain fatty acids into mitochondria and inhibited fatty acid oxidation [ 33 ]. In addition, the lipid composition of mitochondrial membranes was altered with the continuous accumulation of lipids.…”
Section: Mitochondrial Dysfunction and Chronic Liver Diseasementioning
confidence: 99%
“…[ [29][30][31][32][33][34][35][36][37] ROS Oxidative stress occurs, MDA and ROS are increased. [30,32,[35][36][37] mtDNA Mitochondrial biosynthesis is attenuated and mtDNA content is reduced.…”
Mitochondria are generally considered the powerhouse of the cell, a small subcellular organelle that produces most of the cellular energy in the form of adenosine triphosphate (ATP). In addition, mitochondria are involved in various biological functions, such as biosynthesis, lipid metabolism, oxidative phosphorylation, cell signal transduction, and apoptosis. Mitochondrial dysfunction is manifested in different aspects, like increased mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, adenosine triphosphate (ATP) synthesis disorder, abnormal mitophagy, as well as changes in mitochondrial morphology and structure. Mitochondrial dysfunction is related to the occurrence and development of various chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic fatty liver (AFL), and non-alcoholic fatty liver (NAFL). In this review, we summarize and discuss the role and mechanisms of mitochondrial dysfunction in chronic liver disease, focusing on and discussing some of the latest studies on mitochondria and chronic liver disease.
“…When the localization of CD36 is increased, more ACSL1 and CD36 in the mitochondria interact to boost the transfer of additional LCFAs to ACSL1, which in turn promotes FAO and lessens NAFLD by increasing the production of long-chain acyl-CoA ( Figure 1A ). 26 It may be an effective method for the treatment of NAFLD to inhibit CD36 palmitoylation thereby reducing the localization of CD36 in mitochondria. Figure 1 The mechanisms of CD36 in NAFLD.…”
Section: The Role Of Cd36 In the Occurrence And Progression Of Nafldmentioning
confidence: 99%
“…The relationship between palm acylation of CD36 lipid toxicity needs further study. 26 Gaemers IC et al 34 established a mouse model of NAFLD by high-fat liquid diet (HFLD) overfeeding which liver steatosis developed and NASH developed. In the mouse model, adipocytes experienced metabolic changes, which resulted in a decrease in lipid storage capacity and an increase in lipid outflow, which led to lipotoxicity in peripheral organs.…”
Section: The Role Of Cd36 In the Occurrence And Progression Of Nafldmentioning
Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disorders from non-alcoholic fatty liver (NAFL) to the more severe non-alcoholic steatohepatitis (NASH), is the leading etiology of chronic liver disease and its global prevalence is increasing. Hepatic steatosis, a condition marked by an abnormal buildup of triglycerides in the liver, is the precursor to NAFLD. Differentiated cluster 36 (CD36), a scavenger receptor class B protein, is a membrane receptor that recognizes multiple lipid and nonlipid ligands. It is generally agreed that CD36 contributes significantly to hepatic steatosis by taking part in fatty acid uptake as well as triglyceride storage and secretion. While there has not been any conclusive research on how CD36 inhibitors prevent NAFLD from progressing and no clinically approved CD36 inhibitors are currently available for use in NAFLD, CD36 remains a target worthy of further investigation in NAFLD. In recent years, the potential role of natural products acting through CD36 in treating non-alcoholic fatty liver disease has attracted much attention. This paper offers an overview of the pathogenesis of CD36 in NAFLD and summarizes some of the natural compounds or extracts that are currently being investigated for modulating NAFLD via CD36 or the CD36 pathway, providing an alternative approach to the development of CD36-related drugs in NAFLD.
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