Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.
Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Jul;1863(7):688-699. doi: 10.1016/j.bbalip.2018.04.002. Epub 2018 Apr 7.
Obesity often leads non-alcoholic fatty liver disease, insulin resistance and hyperlipidemia. Expression of carboxylesterase CES1 is positively correlated with increased lipid storage and plasma lipid concentration. Here we investigated structural and metabolic consequences of a single nucleotide polymorphism in CES1 gene that results in p.Gly143Glu amino acid substitution. We generated a humanized mouse model expressing CES1 (control), CES1 and catalytically dead CES1 (negative control) in the liver in the absence of endogenous expression of the mouse orthologous gene. We show that the CES1 variant exhibits only 20% of the wild-type lipolytic activity. High-fat diet fed mice expressing CES1 had reduced liver and plasma triacylglycerol levels. The mechanism by which decreased CES1 activity exerts this hypolipidemic phenotype was determined to include decreased very-low density lipoprotein secretion, decreased expression of hepatic lipogenic genes and increased fatty acid oxidation as determined by increased plasma ketone bodies and hepatic mitochondrial electron transport chain protein abundance. We conclude that attenuation of human CES1 activity provides a beneficial effect on hepatic lipid metabolism. These studies also suggest that CES1 is a potential therapeutic target for non-alcoholic fatty liver disease management.
肥胖症常导致非酒精性脂肪肝、胰岛素抵抗和高血脂症。羧酸酯酶 CES1 的表达与脂质储存增加和血浆脂质浓度升高呈正相关。在这里，我们研究了 CES1 基因中单核苷酸多态性的结构和代谢后果，该多态性导致 p.Gly143Glu 氨基酸取代。我们生成了一种在肝脏中表达 CES1（对照）、CES1 和无催化活性 CES1（阴性对照）的人源化小鼠模型，而小鼠同源基因无内源性表达。我们表明，该 CES1 变体仅表现出野生型脂肪分解活性的 20%。表达 CES1 的高脂肪饮食喂养的小鼠肝和血浆三酰甘油水平降低。降低 CES1 活性发挥这种降血脂表型的机制被确定包括降低极低密度脂蛋白的分泌、降低肝脏生脂基因的表达以及增加脂肪酸氧化，这可以通过增加血浆酮体和肝线粒体电子传递链蛋白丰度来确定。我们得出结论，降低人 CES1 活性对肝脏脂质代谢有有益的影响。这些研究还表明，CES1 是治疗非酒精性脂肪性肝病的潜在治疗靶点。
