Open AccessRab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ
Author(s) -
Ziyue Chen,
Yating Sun,
Ziming Wang,
Jie Hong,
Min Xu,
Futing Zhang,
Xianqing Zhou,
Ping Rong,
Qi Wang,
Hong Yu Wang,
Hua Wang,
Shuai Chen,
Liang Chen
Publication year - 2022
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001522
Subject(s) - overnutrition , nonalcoholic fatty liver disease , ampk , biology , fatty liver , endocrinology , medicine , peroxisome proliferator activated receptor , amp activated protein kinase , microbiology and biotechnology , phosphorylation , protein kinase a , disease , receptor , biochemistry , obesity
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.