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GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity
The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulat...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group UK
2021
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636488/ https://www.ncbi.nlm.nih.gov/pubmed/34853313 http://dx.doi.org/10.1038/s41467-021-27309-1 |
| _version_ | 1784608539265728512 |
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| author | Peng, Yumeng Zeng, Qiang Wan, Luming Ma, Enhao Li, Huilong Yang, Xiaopan Zhang, Yanhong Huang, Linfei Lin, Haotian Feng, Jiangyue Xu, Yixin Li, Jingfei Liu, Muyi Liu, Jing Lin, Changqin Sun, Zhiwei Cheng, Gong Zhang, Xuemiao Liu, Jialong Li, Dongrui Wei, Meng Mo, Yunhai Mu, Xuetao Deng, Xiaowei Zhang, Dandan Dong, Siqing Huang, Hanqing Fang, Yi Gao, Qi Yang, Xiaoli Wu, Feixiang Zhong, Hui Wei, Congwen |
| author_facet | Peng, Yumeng Zeng, Qiang Wan, Luming Ma, Enhao Li, Huilong Yang, Xiaopan Zhang, Yanhong Huang, Linfei Lin, Haotian Feng, Jiangyue Xu, Yixin Li, Jingfei Liu, Muyi Liu, Jing Lin, Changqin Sun, Zhiwei Cheng, Gong Zhang, Xuemiao Liu, Jialong Li, Dongrui Wei, Meng Mo, Yunhai Mu, Xuetao Deng, Xiaowei Zhang, Dandan Dong, Siqing Huang, Hanqing Fang, Yi Gao, Qi Yang, Xiaoli Wu, Feixiang Zhong, Hui Wei, Congwen |
| author_sort | Peng, Yumeng |
| collection | PubMed |
| description | The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention. |
| format | Online Article Text |
| id | pubmed-8636488 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2021 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-86364882021-12-15 GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity Peng, Yumeng Zeng, Qiang Wan, Luming Ma, Enhao Li, Huilong Yang, Xiaopan Zhang, Yanhong Huang, Linfei Lin, Haotian Feng, Jiangyue Xu, Yixin Li, Jingfei Liu, Muyi Liu, Jing Lin, Changqin Sun, Zhiwei Cheng, Gong Zhang, Xuemiao Liu, Jialong Li, Dongrui Wei, Meng Mo, Yunhai Mu, Xuetao Deng, Xiaowei Zhang, Dandan Dong, Siqing Huang, Hanqing Fang, Yi Gao, Qi Yang, Xiaoli Wu, Feixiang Zhong, Hui Wei, Congwen Nat Commun Article The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention. Nature Publishing Group UK 2021-12-01 /pmc/articles/PMC8636488/ /pubmed/34853313 http://dx.doi.org/10.1038/s41467-021-27309-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
| spellingShingle | Article Peng, Yumeng Zeng, Qiang Wan, Luming Ma, Enhao Li, Huilong Yang, Xiaopan Zhang, Yanhong Huang, Linfei Lin, Haotian Feng, Jiangyue Xu, Yixin Li, Jingfei Liu, Muyi Liu, Jing Lin, Changqin Sun, Zhiwei Cheng, Gong Zhang, Xuemiao Liu, Jialong Li, Dongrui Wei, Meng Mo, Yunhai Mu, Xuetao Deng, Xiaowei Zhang, Dandan Dong, Siqing Huang, Hanqing Fang, Yi Gao, Qi Yang, Xiaoli Wu, Feixiang Zhong, Hui Wei, Congwen GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| title | GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| title_full | GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| title_fullStr | GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| title_full_unstemmed | GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| title_short | GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| title_sort | gp73 is a tbc-domain rab gtpase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636488/ https://www.ncbi.nlm.nih.gov/pubmed/34853313 http://dx.doi.org/10.1038/s41467-021-27309-1 |
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