BMP6 protects against hepatic inflammation and fibrosis in experimental NASH models

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) starts with hepatic steatosis, which can progress with inflammation to non-alcoholic steatohepatitis (NASH), and a subset of patients develop 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 NAFLD. Methods and Results: BMP6 deficient (BMP6-/-) and 129Sv/Ev wild-type control mice were subjected to two established dietary NASH models: (i) a high fat diet (HFD) and (ii) a methionine choline deficient diet (MCD). BMP6 expression in wild-type mice was markedly increased in both models and BMP6-/- mice exhibited significantly increased hepatic inflammation and fibrosis. Searching for the cellular source and the mechanisms that promote hepatic BMP6 expression we found that hepatocellular lipid accumulation induces BMP6 expression in primary human hepatocytes in vitro. Furthermore, BMP6 expression was analyze in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis. Further, in vitro experiments revealed that recombinant BMP6 inhibits the activation of primary hepatic stellate cells (HSC) and inhibits profibrogenic gene expression in already activated HSCs. Conclusion: Hepatic steatosis induces hepatic BMP6 expression in hepatocytes, which inhibits NASH induced inflammation and fibrosis. These data suggest BMP6 as potential therapeutic target to inhibit the progression of NAFLD.

BMP6 - NASH - mouse model of NAFLD