Group on Molecular and Cell Biology of Lipids University of Alberta, Alberta, Canada; Departments of Pediatrics, University of Alberta, Alberta, Canada.
Instituto de Fisiología Experimental (IFISE), Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Rosario, Argentina.
J Lipid Res. 2019 Apr;60(4):880-891. doi: 10.1194/jlr.M092544. Epub 2019 Feb 8.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated DNL, WT and Ces1d-deficient mice were fed a lipogenic high-sucrose diet (HSD). We found that Ces1d-deficient mice were protected from HSD-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency leads to activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase. Together with our previous demonstration that Ces1d deficiency attenuated high-fat diet-induced steatosis, this study suggests that inhibition of CES1 (the human ortholog of Ces1d) might represent a novel pharmacological target for prevention and treatment of NAFLD.
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病。甘油三酯在肝脏中的积累是非酒精性脂肪性肝病的一个标志。代谢研究证实，人类肝脏中新的脂肪生成（DNL）的增加导致肝脏脂肪堆积，并导致非酒精性脂肪性肝病的进展。缺乏羧基酯酶（Ces）1d 表达的小鼠可防止高脂肪饮食引起的肝脂肪变性。为了研究 Ces1d 的缺失是否也可以减轻由过度激活的 DNL 引起的脂肪变性，我们用富含合成代谢的高蔗糖饮食（HSD）喂养 WT 和 Ces1d 缺陷型小鼠。我们发现 Ces1d 缺陷型小鼠可防止 HSD 诱导的肝内脂质积累。从机制上讲，Ces1d 缺失导致 AMP 激活的蛋白激酶的激活和乙酰辅酶 A 羧化酶的抑制性磷酸化。结合我们之前的研究结果表明 Ces1d 缺乏可减轻高脂肪饮食诱导的脂肪变性，这项研究表明抑制 CES1（Ces1d 的人类同源物）可能是非酒精性脂肪性肝病预防和治疗的一个新的药理学靶点。
