Growth differentiation factor 15 protects against chronic alcohol- and carbon tetrachloride-induced liver injury
Hyon-Seung Yi1
1Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea
Growth differentiation factor 15 (GDF15) has recently been shown to have an important role in the regulation of mitochondrial function and in the pathogenesis of complex human diseases. In previous reports, serum levels of GDF15 were increased in patients with viral hepatitis, tumors, or metabolic diseases compared to healthy controls. Mitochondrial dysfunction was also associated with elevated serum GDF15 levels in mice with obesity or hepatic steatosis or inflammation, which may be a physiologic response to restore metabolic homeostasis. Nevertheless, the role of GDF15 in alcohol-induced or fibrotic liver diseases has yet to be determined. In this study, we demonstrate that alcohol- or carbon tetrachloride (CCl4)-mediated hepatic GDF15 production ameliorates liver inflammation and fibrosis. Alcohol or CCl4 directly enhanced GDF15 expression in primary hepatocytes or liver tissues, which induces the alterations of oxygen consumption rates. Moreover, GDF15 reduced the expression of pro-inflammatory cytokines in liver infiltrating macrophages, leading to an improvement in inflammation and fibrosis in the liver. GDF15 knockout (KO) mice had more TNF-α-producing T cells and more activated CD4+ and CD8+ T cells in the liver than wild-type mice. Liver infiltrating monocytes and neutrophils were also increased in the GDF15 KO mice during liver fibrogenesis induced by CCl4. These changes in the population of hepatic immune cells were associated with increased tissue inflammation and fibrosis in the liver. Finally, recombinant GDF15 decreased the expression of pro-inflammatory cytokines and fibrotic mediators and prevented the activation of T cells in the livers of mice with CCl4-induced liver fibrosis. These results suggest that GDF15 could be a potential therapeutic target for the treatment of alcohol-induced and fibrotic liver diseases.
