Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States of America.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, United States of America.
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Mar;1864(3):358-371. doi: 10.1016/j.bbalip.2018.12.012. Epub 2018 Dec 20.
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.
长链酰基辅酶 A 合成酶 1（ACSL1）在心脏、脂肪组织和骨骼肌的脂肪酸β氧化中发挥关键作用。然而，ACSL1 在肝脏中的关键功能在很大程度上仍然未知。我们研究了肝 ACSL1 缺乏对高脂血症和正常血脂条件下成年小鼠脂质代谢的急性影响。我们使用表达 ACSL1 shRNA 的腺病毒（Ad-shAcsl1）在高脂饮食或正常饮食喂养的小鼠中敲低肝 ACSL1 表达。肝 ACSL1 耗竭在两种饮食喂养的小鼠中产生高胆固醇血症表型，循环总胆固醇、LDL 胆固醇和游离胆固醇显着升高，肝脏胆固醇积累。此外，ACSL1 耗尽的肝脏中 SREBP2 途径受到严重抑制，LDL 受体蛋白水平降低 50%。与胆固醇代谢失调相反，血清甘油三酯、游离脂肪酸和磷脂水平不受影响。全基因组基因表达谱和途径分析的机制研究表明，ACSL1 耗竭抑制了几种胆汁酸生物合成的关键酶的表达，导致肝胆汁酸水平降低和胆汁酸组成改变。这些结果首次证明了 ACSL1 在肝脏组织中胆汁酸生物合成途径中的必需作用。此外，我们发现 Acsl1 是胆汁酸激活法尼醇 X 受体（FXR）的新型分子靶标。激动剂奥贝胆酸激活 FXR 可抑制 FXR 野生型小鼠肝脏中 ACSL1 蛋白和 mRNA 的表达，但不能抑制 FXR 敲除小鼠肝脏中 ACSL1 蛋白和 mRNA 的表达。
