Bone Morphogenetic Protein-8B Expression is Induced in Steatotic Hepatocytes and Promotes Hepatic Steatosis and Inflammation In Vitro

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. The bone morphogenetic protein-8B (BMP8B) has been shown to be expressed in brown adipose tissues and the hypothalamus and to affect thermogenesis and susceptibility to diet-induced obesity. Here, we aimed to analyze BMP8B expression in NAFLD and to gain insight into BMP8B effects on pathophysiological steps of NAFLD progression. BMP8B mRNA and protein expression were dose-dependently induced in primary human hepatocytes in vitro upon incubation with fatty acids. Furthermore, hepatic BMP8B expression was significantly increased in a murine NAFLD model and in NAFLD patients compared with controls. Incubation with recombinant BMP8B further enhanced the fatty acid-induced cellular lipid accumulation as well as NFκB activation and pro-inflammatory gene expression in hepatocytes, while siRNA-mediated BMP8B depletion ameliorated these fatty acid-induced effects. Analysis of the expression of key factors of hepatocellular lipid transport and metabolisms indicated that BMP8B effects on fatty acid uptake as well as de novo lipogenesis contributed to hepatocellular accumulation of fatty acids leading to increased storage in the form of triglycerides and enhanced combustion by beta oxidation. In conclusion, our data indicate that BMP8B enhances different pathophysiological steps of NAFLD progression and suggest BMP8B as a promising prognostic marker and therapeutic target for NAFLD and, potentially, also for other chronic liver diseases.

Keywords

• BMP8B
• steatosis
• inflammation
• NAFLD
• non-alcoholic fatty liver disease