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

营养过剩 非酒精性脂肪肝 安普克 生物 脂肪肝 内分泌学 过氧化物酶体增殖物激活受体 内科学 AMP活化蛋白激酶 人口 细胞生物学 磷酸化 蛋白激酶A 受体 疾病 生物化学 肥胖 医学 环境卫生
作者
Ziyue Chen,Yating Sun,Ziming Wang,Jie Hong,Min Xu,Futing Zhang,Xianqing Zhou,Ping Rong,Qi Wang,Hong Wang,Hua Wang,Shuai Chen,Liang Chen
出处
期刊:PLOS Biology [Public Library of Science]
卷期号:20 (1): e3001522-e3001522 被引量:3
标识
DOI:10.1371/journal.pbio.3001522
摘要

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 TBC1D1S231A-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.
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