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

被引:3
作者
Du, Chongyangzi [1 ]
Yang, Wanchun [1 ,2 ]
Yu, Zongyan [3 ,4 ]
Yuan, Qiuyun [1 ]
Pang, Dejiang [1 ]
Tang, Ping [1 ]
Jiang, Wanxiang [1 ]
Chen, Mina [1 ]
Xiao, Bo [3 ,4 ]
机构
[1] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Neurosci & Metab Res, Chengdu, Peoples R China
[2] Sichuan Univ, West China Hosp, Dept Neurosurg, Chengdu, Peoples R China
[3] Southern Univ Sci & Technol, Sch Life Sci, Shenzhen Key Lab Gene Regulat & Syst Biol, Shenzhen, Peoples R China
[4] Southern Univ Sci & Technol, Brain Res Ctr, Sch Life Sci, Dept Biol, Shenzhen, Peoples R China
基金
中国国家自然科学基金;
关键词
Rheb; triglyceride; VLDL; hepatosteatosis; ATP; FATTY-ACID SYNTHESIS; INHIBITS AUTOPHAGY; GLUCOSE-METABOLISM; HEPATIC STEATOSIS; MTORC1; DISEASE; DICHLOROACETATE; DIFFERENTIATION; MYELINATION; CONTRIBUTES;
D O I
10.3389/fcell.2022.808140
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
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页数:11
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