Abstract 15228: Identification of a Novel Regulatory Pathway for Acyl-CoA Synthetase 1 Expression by Cholesterol Through Tissue Profiling in Cholesterol-Fed Hamsters
Long-chain acyl-CoA synthetases (ACSL) play key roles in fatty acid utilization in all metabolic tissues including heart. Among the 5 ACSL isoforms, ACSL1 is the most abundant one in heart, liver and adipose tissue. Functional studies have revealed a pivotal role of ACSL1 in FA β-oxidation in cardiac and adipose tissues. However, in liver, ACSL1 absence only resulted in small changes in FA compositions of phospholipids and slight reductions in TAG synthesis. Further to ACSL1’s divergent functions in different tissues, its regulation exhibits tissue-specificity. In heart, liver and adipose tissue, ACSL1 expression is elevated by PPARα ligand. In microphages, ACSL1 expression is highly induced by proinflammatory cytokines but does not respond to PPAR activation. Over the past several years, evidence is accumulating to support the notion that the upstream regulatory signaling pathways of different ACSL isoforms impact their tissue-specific functions in channeling FA into different metabolic pathways to meet the body’s energy demand. To gain a deeper understanding of the regulation of ACSL1 under different nutritional status, we first cloned ACSL1 homolog of golden Syrian hamster; next we tissue profiled ACSL1 mRNA and protein expressions in hamsters fed a normal diet (ND), a high fat diet (HF) or a high cholesterol diet (HC). Our study shows that while HF diet had little effects on ACSL1 expression in various organs, HC diet downregulated ACSL1 mRNA and protein levels coordinately in a tissue-specific manner. In testis, amounts of ACSL1 mRNA and protein in HC group were reduced to 25% and 37% of the ND group, respectively. In liver, HC diet lowered ACSL1 mRNA by 41% and protein by 55% as compared to the ND group. In heart and brain, the negative effects of cholesterol on ACSL1 expression were also significant albeit to lesser extents as compared to testis and liver. Interestingly, the expression of ACSL1 mRNA and protein in adipose tissue and skeletal muscle were unchanged by HC diet. Collectively, our study identifies a novel regulatory pathway utilized by cholesterol that modulates ACSL1 cellular abundance in a tissue-specific manner. This work shed new light on the functional role of ACSL1 in hypercholesterolemia, the underlying cause of cardiovascular disease.
- © 2013 by American Heart Association, Inc.