Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver

Du，Chongyangzi1; Yang，Wanchun1,2; Yu，Zongyan3,4; Yuan，Qiuyun1; Pang，Dejiang1; Tang，Ping1; Jiang，Wanxiang1; Chen，Mina1; Xiao，Bo3,4

2022-03-16

10.3389/fcell.2022.808140

Frontiers in Cell and Developmental Biology   影响因子和分区

2296-634X

2296-634X

Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.

ATP hepatosteatosis Rheb triglyceride VLDL

SCI

英语

通讯

National Natural Science Foundation of China[81571195 31501155 31530042 31371484];

Cell Biology ; Developmental Biology

Cell Biology ; Developmental Biology

WOS:000778718500001

FRONTIERS MEDIA SA

2-s2.0-85127596061

Scopus

1.Neuroscience and Metabolism Research,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu,China
2.Department of Neurosurgery,West China Hospital,Sichuan University,Chengdu,China
3.Shenzhen Key Laboratory of Gene Regulation and Systems Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen,China
4.Department of Biology,School of Life Sciences,Brain Research Center,Southern University of Science and Technology,Shenzhen,China

Du，Chongyangzi,Yang，Wanchun,Yu，Zongyan,et al. Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver[J]. Frontiers in Cell and Developmental Biology,2022,10.

Du，Chongyangzi.,Yang，Wanchun.,Yu，Zongyan.,Yuan，Qiuyun.,Pang，Dejiang.,...&Xiao，Bo.(2022).Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver.Frontiers in Cell and Developmental Biology,10.

Du，Chongyangzi,et al."Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver".Frontiers in Cell and Developmental Biology 10(2022).