Luo Pengcheng, Wang Pi-Xiao, Li Zuo-Zhi, Zhang Xiao-Jing, Jiang Xi, Gong Jun, Qin Juan-Juan, Guo Junhong, Zhu Xueyong, Yang Sijun, Li Hongliang
Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Huangshi Central Hospital, Hubei Polytechnic University, Huangshi, China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Am J Pathol. 2016 May;186(5):1278-92. doi: 10.1016/j.ajpath.2015.12.028. Epub 2016 Mar 11.
The liver is an essential insulin-responsive organ that is critical for maintaining glucose homeostasis and lipid metabolism. Oncostatin M receptor β chain (OSMRβ) is implicated in adipose tissue- and immune cell-mediated metabolic regulation. However, the role of hepatocyte-derived OSMRβ in metabolic disorders remains unclear. Here, we report on the central role of OSMRβ in the protection against obesity and deregulation of glucose and lipids. We observed significantly varied expression levels of OSMRβ in hepatic tissues in both human samples and mouse models of nonalcoholic fatty liver disease. Mice lacking either whole-body or hepatic OSMRβ displayed exacerbated diet-induced insulin resistance, hepatic steatosis, and inflammation, both in diet-induced and genetically (ob/ob) obese mice. These adverse effects were markedly attenuated by hepatocyte-specific overexpression of OSMRβ. Mechanistically, we showed that OSMRβ phosphorylates and activates the Janus kinase 2 (JAK2)/STAT3 signaling pathway in the liver. More importantly, the liver-restricted overexpression of STAT3 rescued glucose tolerance and ameliorated hepatic steatosis and inflammation in OSMRβ knockout mice, whereas OSMRβ overexpression failed to protect against hepatic steatosis, insulin resistance, and hepatic inflammation in STAT3-deficient mice. Thus, activation of STAT3 is both sufficient and required to produce OSMRβ-mediated beneficial effects. In conclusion, hepatic OSMRβ expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades.
肝脏是一个重要的胰岛素反应器官，对维持葡萄糖稳态和脂质代谢至关重要。抑瘤素M受体β链（OSMRβ）参与脂肪组织和免疫细胞介导的代谢调节。然而，肝细胞衍生的OSMRβ在代谢紊乱中的作用仍不清楚。在此，我们报告了OSMRβ在预防肥胖以及调节葡萄糖和脂质方面的核心作用。我们在非酒精性脂肪性肝病的人类样本和小鼠模型的肝组织中观察到OSMRβ的表达水平有显著差异。在饮食诱导的肥胖小鼠和基因（ob/ob）肥胖小鼠中，全身或肝脏缺乏OSMRβ的小鼠表现出饮食诱导的胰岛素抵抗、肝脂肪变性和炎症加剧。OSMRβ的肝细胞特异性过表达显著减轻了这些不良反应。从机制上讲，我们表明OSMRβ在肝脏中磷酸化并激活Janus激酶2（JAK2）/信号转导和转录激活因子3（STAT3）信号通路。更重要的是，肝脏特异性过表达STAT3可挽救OSMRβ基因敲除小鼠的葡萄糖耐量，并改善肝脂肪变性和炎症，而在STAT3缺陷小鼠中，OSMRβ过表达未能预防肝脂肪变性、胰岛素抵抗和肝脏炎症。因此，STAT3的激活对于产生OSMRβ介导的有益作用既是充分的也是必要的。总之，肝脏OSMRβ表达通过激活JAK2/STAT3信号级联反应减轻肥胖诱导的肝脏胰岛素抵抗和脂肪变性。
