BMP6 protects against hepatic fibrosis in experimental NASH models

Abstract

A significant number of patients with non-alcoholic fatty disease (NAFLD) develop significant inflammation (NASH) and fibrosis, which may progress to cirrhosis. Different studies have uncovered bone morphogenetic proteins (BMPs) as important molecules being involved in organ fibrosis, however, studies regarding hepatic fibrosis are sparse and mostly focused on BMP7, of which anti-fibrogenic effects have been described. The aim of this study was to analyze the expression and function of BMP6 in NASH induced fibrosis. Methods and Results: BMP6 deficient (BMP6-/-) and 129Sv/Ev wild type control mice (wt) were subjected to two established dietary NASH-models: (i) a high fat diet (HFD; for 3 months) or (ii) a methionine choline deficient diet (MCD; for 5 weeks). In both models hepatic BMP6 expression was markedly increased compared to the control group fed with standard chow. In contrast, no induction of BMP7 was observed. In both models BMP6-/- mice exhibited increased hepatic expression of pro-inflammatory (MCP-1, TNF-alpha) and pro-fibrogenic (TGF-β, Collagen I) genes compared to wt mice. Additionally, alpha-SMA immunohistochemistry revealed activation of hepatic stellate cells (HSC) and reticulin and sirius red staining evidenced significant histological fibrosis. Noteworthy, hepatic inflammation and fibrosis were significantly higher in BMP6-/- mice in both models. Ex vivo analysis showed that neither freshly isolated nor in vitro activated HSC express BMP6. Also in primary hepatocytes basal BMP6 expression is on the detection limit. However and interestingly, in an in vitro model of hepatocellular lipid accumulation we observed a marked up-regulation of BMP6 expression in primary hepatocytes. Conclusion: Hepatic steatosis induces hepatic BMP6 expression, which inhibits NASH induced inflammation and fibrosis. Thus, (recombinant) BMP6 appears as potential therapy to inhibit the progression of NAFLD.