TARGETING FATTY ACID METABOLISM IN OBESITY: ROLE OF FATTY-ACYL-COA SYNTHASE AS A THERAPEUTIC TARGET
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Keywords
Obesity, Fatty Acid Metabolism, Acyl-CoA Synthetases, ACSL4, Therapeutic Target, Metabolic Syndrome, Insulin Resistance.
Abstract
Obesity has emerged as a global pandemic and a primary driver of chronic metabolic diseases, including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). The pathophysiology of obesity is intrinsically linked to the dysregulation of fatty acid metabolism, which fosters ectopic lipid accumulation, cellular lipotoxicity, insulin resistance, and a state of chronic low-grade inflammation. Central to the control of lipid fate are the fatty-acyl-CoA synthases (ACSLs), a family of isoenzymes that catalyze the activation of long-chain fatty acids to their acyl-CoA thioesters. This activation is the committed step that directs fatty acids towards distinct metabolic pathways, such as mitochondrial β-oxidation for energy production or esterification into complex lipids like triglycerides for storage. Accumulating evidence indicates that the expression and activity of specific ACSL isoforms are significantly altered in obesity. In particular, isoforms such as ACSL1, ACSL4, and ACSL5 have been implicated in adipocyte dysfunction, hepatic steatosis, and skeletal muscle insulin resistance. This review consolidates the current understanding of the role of ACSLs in the pathogenesis of obesity and its metabolic sequelae. We discuss the structure, tissue-specific functions, and regulatory mechanisms of key ACSL isoforms. Furthermore, we explore the therapeutic potential of targeting ACSLs, highlighting emerging pharmacological and genetic strategies aimed at developing isoform-specific inhibitors. By serving as critical nodes in the lipid metabolic network, ACSLs represent promising therapeutic targets for the development of novel interventions to combat obesity and its devastating complications.
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Riddhi Sharma
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Mrs. Sonika Maheshwari
Assistant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Mr. Ashish Mishra
Assistant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad