Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ.
Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ.
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Rab 2A通过稳定PPARγ调节AMPK-TBC 1D 1轴下游非酒精性脂肪肝的进展。
DOI：
10.1371/journal.pbio.3001522
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发表时间：
2022-01
期刊：
影响因子：
9.8
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Chen ZY;Sun YT;Wang ZM;Hong J;Xu M;Zhang FT;Zhou XQ;Rong P;Wang Q;Wang HY;Wang H;Chen S;Chen L
非酒精性脂肪肝（NAFLD）影响着全球约四分之一的人口，持续营养过剩是主要原因之一。然而，潜在的分子基础尚未完全阐明，也没有特定的药物已被批准用于这种疾病。在这里，我们确定了一种调控机制，揭示了Rab 2A在能量状态和PPARγ基础上的NAFLD进展中的新功能。机制分析表明，营养补充抑制AMPK-TBC 1D 1信号的磷酸化，增加GTP结合Rab 2A的水平，进而增加PPARγ蛋白的稳定性，最终促进体内外脂质在肝脏的蓄积。此外，我们发现，阻断TBC 1D 1 S231 A-敲入（KI）小鼠中的AMPK-TBC 1D 1通路导致老年小鼠中GTP结合Rab 2A和随后的脂肪肝显著增加。我们的研究还表明，Rab 2A表达抑制减轻西方饮食诱导的肥胖（DIO）小鼠的肝脏脂质沉积，通过降低PPARγ的蛋白水平和PPARγ靶基因的表达。我们的研究结果不仅揭示了在持续营养过剩期间调节NAFLD进展的新分子机制，而且对药物发现具有潜在的意义。非酒精性脂肪性肝病（NAFLD）影响全球约四分之一的人口;持续营养过剩是主要原因之一，但分子机制仍不清楚。这项研究表明，营养过剩抑制AMPK和TBC 1D 1的磷酸化，增加GTP结合Rab 2A的水平，增加PPARγ的稳定性，最终促进脂质在肝脏的积累。
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. Non-alcoholic fatty liver disease (NAFLD) affects approximately a quarter of the global population; persistent overnutrition is one of the major causes, but the molecular mechanism remains unclear. This study shows that overnutrition suppresses the phosphorylation of AMPK and TBC1D1, augmenting the level of GTP-bound Rab2A and increasing the stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids.
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DOI：
10.1002/hep.31568
发表时间：
2021-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Lin Q;Huang Z;Cai G;Fan X;Yan X;Liu Z;Zhao Z;Li J;Li J;Shi H;Kong M;Zheng MH;Conklin DJ;Epstein PN;Wintergerst KA;Mohammadi M;Cai L;Li X;Li Y;Tan Y
通讯作者：
Tan Y
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
15.9
作者：
Matsusue, K;Haluzik, M;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
AMPK-TBC1D1 连接的破坏会增加脂肪生成基因的表达，并通过促进 IGF1 分泌导致小鼠肥胖
DOI：
10.1073/pnas.1600581113
发表时间：
2016-06-28
影响因子：
11.1
作者：
Chen, Liang;Chen, Qiaoli;Chen, Shuai
通讯作者：
Chen, Shuai
影响因子：
29
作者：
Hall JA;Ramachandran D;Roh HC;DiSpirito JR;Belchior T;Zushin PH;Palmer C;Hong S;Mina AI;Liu B;Deng Z;Aryal P;Jacobs C;Tenen D;Brown CW;Charles JF;Shulman GI;Kahn BB;Tsai LTY;Rosen ED;Spiegelman BM;Banks AS
通讯作者：
Banks AS