Hepatic p38 Activation Modulates Systemic Metabolism Through FGF21-Mediated Interorgan Communication
Hepatic p38 Activation Modulates Systemic Metabolism Through FGF21-Mediated Interorgan Communication
复制标题
肝脏 p38 激活通过 FGF21 介导的器官间通讯调节全身代谢
DOI：
10.2337/db21-0240
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发表时间：
2022-01-01
期刊：
影响因子：
7.7
通讯作者：
Ying, Hao
中科院分区：
文献类型：
--
作者：
Liu, Wei;Sun, Chao;Ying, Hao
非酒精性脂肪性肝病中脂肪变性和胰岛素抵抗的发病机制尚不清楚。脂肪肝中p38磷酸化的增加早已被注意到；然而，肝p38的激活是肝脂肪变性的原因还是结果尚不清楚。在这里，我们证明了通过MKK6在小鼠肝脏中过表达激活肝脏p38诱导严重的肝脏脂肪变性，减少脂肪量，并以肝脏p38 α和fgf21依赖的方式提高循环脂肪酸水平。从机制上讲，通过增加肝脏FGF21的产生，肝脏p38激活增加脂肪酸从脂肪组织流入肝脏，导致肝脏异位脂质积累和胰岛素抵抗。尽管肝脏p38激活在外周组织中表现出良好的作用，但它通过促进FGF21受体辅助因子β - klotho的泛素化和降解而损害肝脏FGF21的作用。我们一致表明，当p38磷酸化和FGF21表达增加时，小鼠和患者的脂肪肝中β - klotho蛋白水平降低。总之，我们的研究揭示了先前未描述的肝脏p38激活对全身代谢的影响，并为肝脏p38 α、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。
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 p38 alpha- and FGF21-dependent manner. Mechanistically, through increasing 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 beta-Klotho. Consistently, we show that when p38 phosphorylation and FGF21 expression are increased, beta-Klotho protein levels are decreased in the fatty liver of both mice and 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 p38 alpha, FGF21, and beta-Klotho in the pathogenesis of nonalcoholic fatty liver disease.