GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity.

Abstract

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.

• Authors: Yumeng Peng, Qiang Zeng, Luming Wan, Enhao Ma, Huilong Li, Xiaopan Yang, Yanhong Zhang, Linfei Huang, Haotian Lin, Jiangyue Feng, Yixin Xu, Jingfei Li, Muyi Liu, Jing Liu, Changqin Lin, Zhiwei Sun, Gong Cheng, Xuemiao Zhang, Jialong Liu, Dongrui Li, Meng Wei, Yunhai Mo, Xuetao Mu, Xiaowei Deng, Dandan Zhang, Siqing Dong, Hanqing Huang, Yi Fang, Qi Gao, Xiaoli Yang, Feixiang Wu, Hui Zhong, Congwen Wei
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 7004 (12 01 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34853313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Apob protein, mouse
• Apolipoprotein B-100
• GP73 protein, mouse
• GTPase-Activating Proteins
• Membrane Proteins
• Phosphoproteins

Topics

• Animals
• Apolipoprotein B-100 (metabolism)
• Body Weight
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• GTPase-Activating Proteins (metabolism)
• Gene Expression Regulation
• Gene Knockdown Techniques
• Insulin Resistance
• Liver (pathology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (genetics, metabolism, pathology)
• Obesity (complications)
• Phosphoproteins (genetics, metabolism)
• Transcriptome