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

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 dysfun...

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Autores principales: Du, Chongyangzi, Yang, Wanchun, Yu, Zongyan, Yuan, Qiuyun, Pang, Dejiang, Tang, Ping, Jiang, Wanxiang, Chen, Mina, Xiao, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8965806/
https://www.ncbi.nlm.nih.gov/pubmed/35372326
http://dx.doi.org/10.3389/fcell.2022.808140
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author Du, Chongyangzi
Yang, Wanchun
Yu, Zongyan
Yuan, Qiuyun
Pang, Dejiang
Tang, Ping
Jiang, Wanxiang
Chen, Mina
Xiao, Bo
author_facet Du, Chongyangzi
Yang, Wanchun
Yu, Zongyan
Yuan, Qiuyun
Pang, Dejiang
Tang, Ping
Jiang, Wanxiang
Chen, Mina
Xiao, Bo
author_sort Du, Chongyangzi
collection PubMed
description 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.
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spelling pubmed-89658062022-03-31 Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver Du, Chongyangzi Yang, Wanchun Yu, Zongyan Yuan, Qiuyun Pang, Dejiang Tang, Ping Jiang, Wanxiang Chen, Mina Xiao, Bo Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2022-03-16 /pmc/articles/PMC8965806/ /pubmed/35372326 http://dx.doi.org/10.3389/fcell.2022.808140 Text en Copyright © 2022 Du, Yang, Yu, Yuan, Pang, Tang, Jiang, Chen and Xiao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Du, Chongyangzi
Yang, Wanchun
Yu, Zongyan
Yuan, Qiuyun
Pang, Dejiang
Tang, Ping
Jiang, Wanxiang
Chen, Mina
Xiao, Bo
Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
title Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
title_full Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
title_fullStr Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
title_full_unstemmed Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
title_short Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
title_sort rheb promotes triglyceride secretion and ameliorates diet-induced steatosis in the liver
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8965806/
https://www.ncbi.nlm.nih.gov/pubmed/35372326
http://dx.doi.org/10.3389/fcell.2022.808140
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