| First Author | He Y | Year | 2019 |
| Journal | Hepatology | PubMed ID | 30964207 |
| Mgi Jnum | J:273129 | Mgi Id | MGI:6287331 |
| Doi | 10.1002/hep.30645 | Citation | He Y, et al. (2019) MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Hepatology |
| abstractText | Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from simple steatosis to more severe forms of liver injury including nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). In humans, only 20-40% of patients with fatty liver progress to NASH, and mice fed a high-fed diet (HFD) develop fatty liver but are resistant to NASH development. To understand how simple steatosis progresses to NASH, we examined hepatic expression of anti-inflammatory microRNA-223 (miR-223) and found that this miRNA was highly elevated in hepatocytes in HFD-fed mice and in human NASH samples. Genetic deletion of the miR-223 induced a full spectrum of NAFLD in long-term HFD-fed mice including steatosis, inflammation, fibrosis and HCC. Furthermore, microarray analyses revealed that compared to wild-type mice, HFD-fed miR-223 knockout (miR-223KO) mice had greater hepatic expression of many inflammatory genes and cancer-related genes, including (C-X-C motif) chemokine 10 (Cxcl10) and transcriptional co-activator with PDZ-binding motif (Taz), two well-known factors to promote NASH development. In vitro experiments demonstrated that Cxcl10 and Taz are two downstream targets of miR-223 and overexpression of miR-223 reduced their expression in cultured hepatocytes. Hepatic levels of miR-223, CXCL10 and TAZ mRNA were elevated in human NASH samples, which positively correlated with hepatic levels of several miR-223 targeted genes as well as several pro-inflammatory, cancer-related and fibrogenic genes. CONCLUSION: HFD-fed miR-223KO mice develop a full spectrum of NAFLD, representing a clinically relevant mouse NAFLD model. MiR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression. MiR-223 may be a novel therapeutic target for the treatment of NASH. This article is protected by copyright. All rights reserved. |
