Journal Article

Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ

Chen, Liang, Xu, Min, Chen, Shuai, Rong, Ping, Wang, Zi-Ming, Zhang, Fu-Ting, Zhou, Xian-Qing, Wang, Qi, Chen, Zi-Yue, Sun, Ya-Ting, Hong, Jie, Wang, Hong Yu, Wang, Hua

2022

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine / Aging / AMP-Activated Protein Kinases - metabolism / Animals / Biology and Life Sciences / Body fat / Diabetes / Energy balance / Fatty acids / Fatty liver / Gene expression / Gene Expression Regulation / Gene Knock-In Techniques / GTPase-Activating Proteins - metabolism / Hep G2 Cells / Humans / Insulin / Kinases / Lipid Metabolism - physiology / Lipids / Liver / Liver diseases / Medicine and Health Sciences / Metabolism / Mice / Non-alcoholic Fatty Liver Disease - metabolism / Non-alcoholic Fatty Liver Disease - pathology / Nutrition / Obesity / Overnutrition / Peroxisome proliferator-activated receptors / Phosphorylation / PPAR gamma - genetics / PPAR gamma - metabolism / Proteins / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / Regulatory mechanisms (biology) / Research and Analysis Methods / Transcription factors