| First Author | Lee SM | Year | 2021 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 11 |
| Issue | 5 | Pages | 1291-1311 |
| PubMed ID | 33444819 | Mgi Jnum | J:347031 |
| Mgi Id | MGI:6808511 | Doi | 10.1016/j.jcmgh.2021.01.003 |
| Citation | Lee SM, et al. (2021) Hepatocyte-Specific Loss of PPARgamma Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver. Cell Mol Gastroenterol Hepatol 11(5):1291-1311 |
| abstractText | BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARgamma) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARgamma plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. METHODS: Hepatocyte-specific PPARgamma expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS: HFCF diet increased PPARgamma expression in hepatocytes, and rosiglitazone further activated PPARgamma in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARgamma reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARgamma-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARgamma plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS: Because of the negative effect of hepatocyte PPARgamma in NASH, inhibition of mechanisms promoted by endogenous PPARgamma in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD. |
