PGC1 alpha protects against hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response
PGC1 alpha protects against hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response
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PGC1 α 通过增强 IL10 介导的抗炎反应来预防肝脂肪变性和胰岛素抵抗
DOI：
10.1096/fj.201902476r
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Ju Zhenyu
中科院分区：
文献类型：
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作者：
Wan Xingyong;Zhu Xudong;Wang Hu;Feng Ye;Zhou Weihua;Liu Peihao;Shen Weiyan;Zhang Lingling;Liu Leiming;Li Tangliang;Diao Daojun;Yang Fan;Zhao Qi;Chen Li;Ren Jian;Yan Sheng;Li Jing;Yu Chaohui;Ju Zhenyu
炎症反应是肝脏代谢紊乱的关键发生率。然而，其潜在机制仍然难以确定。本研究旨在评价过氧化物酶体增殖物激活受体-γ，辅激活因子1 α（PGC 1 α）在IL 10介导的抗炎反应中的作用，以及其在肝脂肪变性和胰岛素抵抗中的作用。对肝细胞特异性PGC 1 α敲入（LivPGC 1 α）小鼠和对照小鼠饲喂高脂饲料（HFD）8周。将IL-10中和抗体注射到PGC 1 α小鼠的肝脏中。采用多种生物学和组织学方法评估肝功能。我们证明，在喂食HFD的小鼠中，肝脏PGC 1 α表达显著降低。LivPGC 1 α肝脏表现出涉及线粒体功能的基因表达增强，并有利于HFD后脂质代谢加速。同时，LivPGC 1 α小鼠显示肝脏脂肪变性和胰岛素抵抗改善。在机制上，PGC 1 α结合并激活IL-10的启动子区域，从而减弱肝脏中的炎症反应。对LivPGC 1 α小鼠给予IL 10中和抗体可消除小鼠中PGC 1 α介导的抗炎作用。此外，IL-10中和抗体干预加重了LivPGC 1 α小鼠的肝脂肪变性和胰岛素抵抗。综上所述，我们的数据表明，肝脏特异性PGC 1 α过表达通过增强IL 10介导的抗炎反应在调节肝脏脂肪变性和胰岛素抵抗中发挥有益作用。PGC 1 α-IL 10轴的药理学激活可能对脂肪肝疾病的治疗有希望。
Inflammatory responses are pivotal incidences in hepatic metabolic derangements. However, the underlying mechanism remains elusive. The present study aimed to evaluate the role of peroxisome proliferator‐activated receptor‐gamma, coactivator 1 alpha (PGC1α) in IL10‐mediated anti‐inflammatory response, and its role in hepatic steatosis and insulin resistance. Hepatocyte‐specific PGC1α knock‐in (LivPGC1α) mice and the control mice were fed high‐fat diet (HFD) for 8 weeks. IL‐10 neutralizing antibody was injected into the liver of PGC1α mice. A variety of biological and histological approaches were applied to assess hepatic function. We demonstrated that hepatic PGC1α expression was significantly reduced in mice fed HFD. LivPGC1α livers exhibited enhanced gene expressions involving mitochondrial function, and favored an accelerated lipid metabolism upon HFD. Meanwhile, LivPGC1α mice revealed improved hepatic steatosis and insulin resistance. Mechanistically, PGC1α bound and activated the promotor region of IL‐10, thereby attenuating inflammatory response in the liver. Administration of IL10 neutralizing antibody to LivPGC1α mice abolished PGC1α‐mediated anti‐inflammatory effects in mice. Further, IL‐10 neutralizing antibody intervention aggravated hepatic steatosis and insulin resistance in LivPGC1α mice. Taken together, our data indicated that hepatic‐specific overexpression of PGC1α exerts a beneficial role in the regulation of hepatic steatosis and insulin resistance via enhancing IL10‐mediated anti‐inflammatory response. Pharmacological activation of PGC1α‐IL10 axis may be promising for the treatment of fatty liver diseases.