Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation[S]
Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation[S]
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DOI：
10.1194/jlr.m092544
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发表时间：
2019-04-01
影响因子：
6.5
通讯作者：
Lehner, Richard
中科院分区：
文献类型：
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作者：
Lian, Jihong;Watts, Russell;Lehner, Richard
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病。三酰甘油在肝脏中的积累是NAFLD的标志。代谢研究已经证实，人类肝脏新生脂肪生成（DNL）的增加有助于肝脏中的脂肪积累和NAFLD进展。羧酸酯酶（Ces）1d表达缺陷的小鼠可免受高脂饮食诱导的肝脂肪变性。为了研究Ces 1d的缺失是否也可以减轻过度活化DNL诱导的脂肪变性，WT和Ces 1d缺陷小鼠喂食生脂高糖饮食（HSD）。我们发现，Ces 1d缺陷的小鼠受到保护，从HSD-induced肝脂质积累。从机制上讲，Ces 1d缺乏导致AMP激活蛋白激酶的激活和乙酰辅酶A羧化酶的抑制磷酸化。结合我们先前的Ces 1d缺乏减弱高脂饮食诱导的脂肪变性的证明，这项研究表明，抑制CES 1（Ces 1d的人类直系同源物）可能代表预防和治疗NAFLD的新药理学靶点。
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.