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Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ
Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we iden...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809606/ https://www.ncbi.nlm.nih.gov/pubmed/35061665 http://dx.doi.org/10.1371/journal.pbio.3001522 |
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author | Chen, Zi-Yue Sun, Ya-Ting Wang, Zi-Ming Hong, Jie Xu, Min Zhang, Fu-Ting Zhou, Xian-Qing Rong, Ping Wang, Qi Wang, Hong Yu Wang, Hua Chen, Shuai Chen, Liang |
author_facet | Chen, Zi-Yue Sun, Ya-Ting Wang, Zi-Ming Hong, Jie Xu, Min Zhang, Fu-Ting Zhou, Xian-Qing Rong, Ping Wang, Qi Wang, Hong Yu Wang, Hua Chen, Shuai Chen, Liang |
author_sort | Chen, Zi-Yue |
collection | PubMed |
description | Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1(S231A)-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease. |
format | Online Article Text |
id | pubmed-8809606 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88096062022-02-03 Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ Chen, Zi-Yue Sun, Ya-Ting Wang, Zi-Ming Hong, Jie Xu, Min Zhang, Fu-Ting Zhou, Xian-Qing Rong, Ping Wang, Qi Wang, Hong Yu Wang, Hua Chen, Shuai Chen, Liang PLoS Biol Research Article Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1(S231A)-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease. Public Library of Science 2022-01-21 /pmc/articles/PMC8809606/ /pubmed/35061665 http://dx.doi.org/10.1371/journal.pbio.3001522 Text en © 2022 Chen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Chen, Zi-Yue Sun, Ya-Ting Wang, Zi-Ming Hong, Jie Xu, Min Zhang, Fu-Ting Zhou, Xian-Qing Rong, Ping Wang, Qi Wang, Hong Yu Wang, Hua Chen, Shuai Chen, Liang Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ |
title | Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ |
title_full | Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ |
title_fullStr | Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ |
title_full_unstemmed | Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ |
title_short | Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ |
title_sort | rab2a regulates the progression of nonalcoholic fatty liver disease downstream of ampk-tbc1d1 axis by stabilizing pparγ |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809606/ https://www.ncbi.nlm.nih.gov/pubmed/35061665 http://dx.doi.org/10.1371/journal.pbio.3001522 |
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