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PGC1α protects against hepatic steatosis and insulin resistance via enhancing IL10‐mediated anti‐inflammatory response
Author(s) -
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
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902476r
Subject(s) - steatosis , insulin resistance , medicine , endocrinology , fatty liver , interleukin 10 , insulin , peroxisome proliferator activated receptor , biology , receptor , cytokine , disease
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.