The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs
The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs
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DOI：
10.1016/j.ejphar.2022.174959
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发表时间：
2022-04-29
影响因子：
5
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Wu, Guanglu;Dai, Yufeng;Chen, Wei
乳酸受体G蛋白偶联受体81(GPR81)最近被认为与脂肪组织的脂肪分解有关。在本研究中，我们偶然发现了GPR81在肝脂代谢中的作用。数据清楚地表明，肝脏GPR81在禁食小鼠中显著上调，而在肥胖小鼠中严重下调。在急性禁食条件下，GPR81基因缺陷会损害生酮反应，增加肝脏脂肪堆积，并加重肝骨病。我们从机制上证明了肝脏GPR81可能作为过氧化物酶体增殖物激活受体-γ共激活物-1α(PGC-1α)的调节剂，激活肝脏肉碱O-棕榈酰基转移酶1(L-CPT1)的下游转录，从而控制脂肪酸进入线粒体进行8-氧化。重要的是，二甲双胍以GPR81依赖的方式改善实验性非酒精性脂肪性肝病(NAFLDs)。总之，GPR81对肝脏脂类平衡至关重要，激活肝脏GPR81可能是治疗肥胖及其相关代谢紊乱的一种有前途的策略。
The lactate receptor G protein-coupled receptor 81 (GPR81) has been recently implicated in lipolysis in adipose tissue. In this study, we accidently discovered the role of GPR81 in hepatic lipid metabolism. Data clearly showed that hepatic GPR81 was markedly up-regulated in fasted mice, whereas it was severely down-regulated in obese mice. Genetic deficiency of GPR81 impaired ketogenic response, enhanced hepatic lipid accumulation, and exacerbated hepatosteatosis under acute fasting conditions. Mechanically, we demonstrated that hepatic GPR81 might function as a modulator of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), activate the downsream transcription of liver carnitine o-palmitoyltransferase 1(L-CPT1), and thereby control the influx of fatty acids into mitochondria for 8-oxidation. Importantly, metformin improved experimental nonalcoholic fatty liver disease (NAFLDs) in a GPR81-dependent manner. Collectively, GPR81 was critical for hepatic lipid homeostasis and activation of hepatic GPR81 might represent a promising strategy for the treatment of obesity and its associated metabolic disorders.