ACSL5

Long-chain acyl-CoA synthetase ACSL5 activates long-chain fatty acids by thioesterification with CoA, generating fatty acyl-CoAs for lipid synthesis and β-oxidation^[1][2]. ACSL5 localizes to the endoplasmic reticulum and mitochondrial outer membrane, where it catalyzes C16-C20 fatty acid conversion into acyl-CoA intermediates^[1]. Mechanistically, ACSL5 supports fatty acid metabolism in liver, small intestine, adipose tissue, and skeletal muscle, with effects depending on substrate preference, subcellular localization, and tissue specificity^[1]. In intestinal epithelium, ACSL5 is the major ACSL isoform and contributes approximately 80% of total ACSL activity, linking dietary fat absorption to enteroendocrine GLP-1 and PYY secretion^[3]. In ACSL5-deficient mice, reduced adiposity, improved insulin sensitivity, increased energy expenditure, delayed triglyceride absorption, and elevated FGF21 define a metabolic model for obesity and insulin-resistance research^[4]. In steatotic human liver and hepatocyte models, fatty acid uptake increases ACSL5 expression, and ACSL5 overexpression increases susceptibility to TRAIL- and TNFα-induced apoptosis through caspase activation and sphingolipid remodeling^[5][6]. Compared with related ACSL isoforms, ACSL5 shows isoform-specific biology because individual ACSLs channel fatty acids into different metabolic pathways, while ACSL3 and ACSL4, but not ACSL5, support glucose-stimulated insulin secretion in β-cell models^[7][8]. Current literature supports ACSL5 genetic, knockdown, overexpression, and tissue-specific ablation models, but does not establish validated ACSL5-selective agonists or inhibitors^[3][4][5][6].