Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance.
Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance.
复制标题
人类羧酸酯酶2逆转肥胖引起的二酰基甘油的积累和葡萄糖不耐症。
DOI：
10.1016/j.celrep.2016.12.070
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发表时间：
2017-01-17
期刊：
影响因子：
8.8
通讯作者：
Zierath JR
中科院分区：
文献类型：
--
作者：
Ruby MA;Massart J;Hunerdosse DM;Schönke M;Correia JC;Louie SM;Ruas JL;Näslund E;Nomura DK;Zierath JR
丝氨酸水解酶是已知影响肥胖的一大类多功能酶。在这里，我们进行了基于活性的蛋白质分析，以评估瘦人和肥胖人肝脏活检中丝氨酸水解酶的功能水平，以获得代谢疾病病理生理学的机制见解。我们发现肥胖人群中羧酸酯酶 2 (CES2) 和芳基乙酰胺脱乙酰酶 (AADAC) 的肝脏活性降低。在原代人肝细胞中，CES2 敲低会损害葡萄糖储存和脂质氧化。在小鼠中，肥胖会降低 CES2，而人类 CES2 的腺病毒递送可逆转肝脂肪变性，改善葡萄糖耐量并减少炎症。脂质组学分析发现了 CES2 调节的脂质网络在人类和小鼠肥胖中发生了改变。 CES2 具有甘油三酯和二酰甘油脂肪酶活性，并与人类 HOMA-IR 和肝二酰甘油浓度呈负相关。因此，CES2减少是肥胖的一个保守特征，并且在肥胖相关代谢紊乱的发病机制中发挥着致病作用。肥胖会降低人类 AADAC 和 CES2 的肝脏活性 CES2 耗竭会损害人类原代肝细胞中的脂质和葡萄糖代谢 人类 CES2 表达可逆转小鼠的肝脏脂肪变性和葡萄糖耐受不良 CES2 控制人类和小鼠肥胖症中的肝脂质网络失调 Ruby 等人。利用基于活性的蛋白质分析来发现肥胖人群肝脏中芳基乙酰胺脱乙酰酶和羧酸酯酶 2 活性的降低。羧酸酯酶 2 控制人类肥胖中失调的脂质网络，从而逆转高脂肪喂养小鼠的肝脂肪变性、葡萄糖不耐受并减少炎症。
Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances. Obesity decreases hepatic activity of AADAC and CES2 in humans CES2 depletion impairs lipid and glucose metabolism in primary human hepatocytes Human CES2 expression reverses hepatic steatosis and glucose intolerance in mice CES2 controls a hepatic lipid network dysregulated in human and mouse obesity Ruby et al. utilize activity-based protein profiling to discover decreased arylacetamide deacetylase and carboxylesterase 2 activities in livers from obese humans. Carboxylesterase 2 controls a lipid network dysregulated in human obesity to reverse hepatic steatosis, glucose intolerance, and decrease inflammation in high-fat fed mice.