| First Author | Wan X | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 8 | Pages | 10751-10761 |
| PubMed ID | 32633848 | Mgi Jnum | J:304229 |
| Mgi Id | MGI:6694437 | Doi | 10.1096/fj.201902476R |
| Citation | Wan X, et al. (2020) PGC1alpha protects against hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response. FASEB J 34(8):10751-10761 |
| abstractText | 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 (PGC1alpha) in IL10-mediated anti-inflammatory response, and its role in hepatic steatosis and insulin resistance. Hepatocyte-specific PGC1alpha knock-in (LivPGC1alpha) mice and the control mice were fed high-fat diet (HFD) for 8 weeks. IL-10 neutralizing antibody was injected into the liver of PGC1alpha mice. A variety of biological and histological approaches were applied to assess hepatic function. We demonstrated that hepatic PGC1alpha expression was significantly reduced in mice fed HFD. LivPGC1alpha livers exhibited enhanced gene expressions involving mitochondrial function, and favored an accelerated lipid metabolism upon HFD. Meanwhile, LivPGC1alpha mice revealed improved hepatic steatosis and insulin resistance. Mechanistically, PGC1alpha bound and activated the promotor region of IL-10, thereby attenuating inflammatory response in the liver. Administration of IL10 neutralizing antibody to LivPGC1alpha mice abolished PGC1alpha-mediated anti-inflammatory effects in mice. Further, IL-10 neutralizing antibody intervention aggravated hepatic steatosis and insulin resistance in LivPGC1alpha mice. Taken together, our data indicated that hepatic-specific overexpression of PGC1alpha exerts a beneficial role in the regulation of hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response. Pharmacological activation of PGC1alpha-IL10 axis may be promising for the treatment of fatty liver diseases. |
