Liu Wei, Sun Chao, Yan Ying, Cao Hongchao, Niu Zhoumin, Shen Siyi, Liu Shengnan, Wu Yuting, Li Yan, Hui Lijian, Li Yuying, Zhao Lin, Hu Cheng, Ding Qiurong, Jiang Jingjing, Ying Hao
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of 1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Sciences; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.
Diabetes. 2021 Oct 21. doi: 10.2337/db21-0240.
The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor β-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expffression are increased, β-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38α, FGF21, and β-Klotho in the pathogenesis of nonalcoholic fatty liver disease.
非酒精性脂肪性肝病中脂肪变性和胰岛素抵抗发病机制的潜在机制仍不清楚。长期以来，人们一直注意到脂肪肝中肝脏p38磷酸化增加；然而，肝脏p38的激活是肝脏脂肪变性的原因还是结果尚不清楚。在这里，我们证明，通过在小鼠肝脏中过表达MKK6激活肝脏p38，以肝脏p38α和FGF21依赖的方式诱导严重的肝脏脂肪变性，减少脂肪量，并提高循环脂肪酸水平。从机制上讲，通过增加肝脏中FGF21的产生，肝脏p38激活增加了脂肪酸从脂肪组织向肝脏的流入，导致肝脏异位脂质积累和胰岛素抵抗。虽然肝脏p38激活在外周组织中表现出有利作用，但它通过促进FGF21受体辅因子β-klotho的泛素化和降解来损害肝脏FGF21的作用。一致地，我们表明，在小鼠或患者的脂肪肝中，p38磷酸化和FGF21表达增加，β-klotho蛋白水平降低。总之，我们的研究揭示了肝脏p38激活对全身代谢的前所未有的影响，并为肝脏p38α、FGF21和β-klotho在非酒精性脂肪性肝病发病机制中的作用提供了新的见解。
