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Identification of a novel function of hepatic long-chain acyl-CoA synthetase-1 (ACSL1) in bile acid synthesis and its regulation by bile acid-activated farnesoid X receptor

Singh, Amar Bahadur, Dong, Bin, Xu, Yanyong, Zhang, Yanqiao, Liu, Jingwen
Biochimica et biophysica acta 2019 v.1864 no.3 pp. 358-371
Adenoviridae, acute effects, acyl coenzyme A, adipose tissue, adults, agonists, beta oxidation, bile, bile acids, biochemical pathways, biosynthesis, blood serum, cholesterol metabolism, fatty acids, free fatty acids, gene expression regulation, heart, high fat diet, hypercholesterolemia, knockout mutants, liver, long-chain-fatty-acid-CoA ligase, low density lipoprotein cholesterol, low density lipoprotein receptors, messenger RNA, mice, phenotype, phospholipids, protein content, skeletal muscle, triacylglycerols
Long-chain acyl-CoA synthetase 1 (ACSL1) plays a pivotal role in fatty acid β‑oxidation in heart, adipose tissue and skeletal muscle. However, key functions of ACSL1 in the liver remain largely unknown. We investigated acute effects of hepatic ACSL1 deficiency on lipid metabolism in adult mice under hyperlipidemic and normolipidemic conditions. We knocked down hepatic ACSL1 expression using adenovirus expressing a ACSL1 shRNA (Ad-shAcsl1) in mice fed a high-fat diet or a normal chow diet. Hepatic ACSL1 depletion generated a hypercholesterolemic phenotype in mice fed both diets with marked elevations of total cholesterol, LDL-cholesterol and free cholesterol in circulation and accumulations of cholesterol in the liver. Furthermore, SREBP2 pathway in ACSL1 depleted livers was severely repressed with a 50% reduction of LDL receptor protein levels. In contrast to the dysregulated cholesterol metabolism, serum triglycerides, free fatty acid and phospholipid levels were unaffected. Mechanistic investigations of genome-wide gene expression profiling and pathway analysis revealed that ACSL1 depletion repressed expressions of several key enzymes for bile acid biosynthesis, consequently leading to reduced liver bile acid levels and altered bile acid compositions. These results are the first demonstration of a requisite role of ACSL1 in bile acid biosynthetic pathway in liver tissue. Furthermore, we discovered that Acsl1 is a novel molecular target of the bile acid-activated farnesoid X receptor (FXR). Activation of FXR by agonist obeticholic acid repressed the expression of ACSL1 protein and mRNA in the liver of FXR wild-type mice but not in FXR knockout mice.