摘要
Nonalcoholic fatty liver disease(NAFLD)encompasses a spectrum of pathologies,ranging from steatosis to nonalcoholic steatohepatitis(NASH).The factors promoting the progression of steatosis to NASH are still unclear.Recent studies suggest that mitochondrial lipid composition is critical in NASH develop-ment.Here,we showed that CDP-DAG synthase 2(Cds2)was downregulated in genetic or diet-induced NAFLD mouse models.Liver-specific deficiency of Cds2 provoked hepatic steatosis,inflammation and fibrosis in five-week-old mice.CDS2 is enriched in mitochondria-associated membranes(MAMs),and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE levels.Overexpression of phosphatidylserine decarboxylase(PISD)alleviated the NASH-like phenotype in Cds2^(f/f);AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in hepatocytes.Additionally,dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha(PPARa)attenuated mitochondrial defects and ameliorated the NASH-like phe-notype in Cds2^(f/f);AlbCre mice.Finally,Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and obesity.Thus,Cds2 modulates mitochondrial function and NASH development.
非酒精性脂肪性肝病(NAFLD)包括单纯脂肪浸润和非酒精性脂肪性肝炎(NASH),继续发展可导致更为严重的肝纤维化、肝硬化和肝癌等.诱导肝脏从单纯脂肪浸润发展成NASH的机制还不是特别清楚.本研究构建了肝脏特异敲除CDP-二酰基甘油合成酶-2(Cds2)小鼠,并发现该小鼠快速产生肝脏脂肪大量储积、肝炎和肝纤维化等一系列肝脏病变.CDS2定位在线粒体相关内质网膜(MAM)上,敲除Cds2会导致线粒体功能受损和线粒体磷脂酰乙醇胺含量下降.肝脏过表达线粒体磷脂酰乙醇胺合成酶(Pisd)会增加线粒体磷脂酰乙醇胺含量,并减轻肝脏Cds2敲除小鼠肝损伤的表型.另外,过表达Cds2可以抵抗高脂喂食诱导的脂肪肝和肥胖.本研究揭示了小鼠肝脏Cds2生理功能,即Cds2可以调节线粒体磷脂含量和线粒体功能并继而影响NASH的快速发生.
作者
iesi Xu
Siyu Chen
Wei Wang
Sin Man Lam
Yang Xu
Shaohua Zhang
Huimin Pan
Jingjing Liang
Xiahe Huang
Yu Wang
Ting Li
Yuqiang Jiang
Yingchun Wang
Mei Ding
Guanghou Shui
Hongyuan Yang
Xun Huang
许捷思;陈思宇;王威;林茜雯;徐扬;张少华;潘慧敏;梁晶晶;黄夏禾;王瑜;李婷;降雨强;汪迎春;丁梅;税光厚;杨洪远;黄勋(State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China;Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences,Beijing 100050,China;School of Biotechnology and Biomolecular Sciences,University of New South Wales,Sydney,New South Wales 2052,Australia)
基金
the Ministry of Science and Technology of China(2018YFA0506902,2016YFA0500100,and 2018YFA081104)
the National Natural Science Foundation of China(9195420001,31771305,and 31630019)
Chinese Academy of Sciences(XDPB17)。
