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Abstract
Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.
Highlights
The prevalence of non-alcoholic fatty liver disease (NAFLD) in adults exceeds 30% in Western countries and Non-alcoholic fatty liver disease (NAFLD) portends increased risk of cardiovascular disease[1,2,3]
Bone morphogenetic protein (BMP) signaling is involved in the pathophysiology of hepatic fibrosis, the role of BMP signaling in the pathophysiology of simple steatosis has not been well elucidated[19,20,21]
We report three novel findings that highlight the importance of BMP signaling in the development of NAFLD: treating db/db mice with BMP inhibitors significantly reduces hepatic steatosis; BMP signaling regulates hepatic Diacylglycerol O-acyltransferase 2 (DGAT2) expression and activity; and a rare single nucleotide polymorphism (SNP) in a BMP type I receptor results in constitutive activation and is associated with NAFLD in humans
Summary
The prevalence of non-alcoholic fatty liver disease (NAFLD) in adults exceeds 30% in Western countries and NAFLD portends increased risk of cardiovascular disease[1,2,3]. We report three novel findings that highlight the importance of BMP signaling in the development of NAFLD: treating db/db mice with BMP inhibitors significantly reduces hepatic steatosis; BMP signaling regulates hepatic DGAT2 expression and activity; and a rare single nucleotide polymorphism (SNP) in a BMP type I receptor results in constitutive activation and is associated with NAFLD in humans. Together, these results provide in vivo, in vitro, and human genetic evidence for the role of BMP signaling in NAFLD and suggest a potential role for drugs targeting the BMP signaling pathway in the treatment of NAFLD
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