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Hepatocyte-specific expression of human carboxylesterase 2 attenuates nonalcoholic steatohepatitis in mice

机译:人羧基酯酶2的肝细胞特异性表达衰减小鼠中的非酒精脂肪骨膜炎

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Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were intravenously injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced nonalcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/ db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic tri-glyceride (T) and free fatty acid (FFA) levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis, and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD.
机译:人羧酸酯酶2(CES2)具有三酰甘油水解酶(TGH)活性,在脂肪分解中起重要作用。在这项研究中,我们旨在确定人类CES2在饮食诱导或基因肥胖小鼠脂肪性肝炎进展或逆转中的作用。高脂/高胆固醇/高果糖(HFCF)饮食喂养的C57BL/6小鼠或db/db小鼠在白蛋白启动子的控制下静脉注射表达人类CES2的腺相关病毒。人CES2在C57BL/6J小鼠中对HFCF饮食诱导的非酒精性脂肪肝(NAFLD)具有保护作用,在db/db小鼠中可逆转脂肪性肝炎。人类CES2也改善了葡萄糖耐受性和胰岛素敏感性。从机理上讲,人类CES2通过诱导脂肪分解和脂肪酸氧化,并通过抑制甾醇调节元件结合蛋白1抑制脂肪生成,从而降低肝脏三甘油酯(T)和游离脂肪酸(FFA)水平。此外,人类CES2的过度表达改善了线粒体呼吸和糖酵解功能,并抑制了糖异生、脂质过氧化、凋亡和炎症。我们的数据表明,人CES2的肝细胞特异性表达可以预防和逆转脂肪性肝炎。靶向肝脏CES2可能是治疗NAFLD的一个有吸引力的策略。

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