Abstract
Liver has numerous critical metabolic functions including lipid metabolism, which is usually dysregulated in obesity, the metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates bone morphogenetic proteins (BMPs) play an important role in adipogenesis and thermogenic balance in adipogenic progenitors and adipose tissue. However, the direct impact of BMPs on hepatic steatosis and possible association with NAFLD are poorly understood. Here, we found that BMP4 was up-regulated in oleic acid-induced steatosis and during the development of high fat diet (HFD)-induced NAFLD. Exogenous BMP4 reduced lipid accumulation and up-regulated the genes involved in lipid synthesis, storage and breakdown in hepatocytes. Exogenous BMP4 inhibited hepatic steatosis, reduced serum triglyceride levels and body weight, and alleviated progression of NAFLD in vivo. Mechanistically, BMP4 overexpression in hepatocytes down-regulated most components of the mTORC1 signaling axis. Collectively, these findings strongly suggest that BMP4 may play an essential role in regulating hepatic lipid metabolism and the molecular pathogenesis of NAFLD. Manipulating BMP4 and/or mTORC1 signaling axis may lead to the development of novel therapeutics for obesity, metabolic syndrome, and NAFLD.
Highlights
Liver is an essential organ in carrying out critical metabolic functions, ranging from metabolism of nutrients, synthesis of glucose and lipids, to detoxification of drugs and xenobiotics
Using Western blotting analysis, we found BMP4 expression in the liver samples was significantly up-regulated in the high fat diet (HFD) group at week 16 and 24, compared with that of the control group (Figure 1C, a)
These results suggest that BMP4 expression may be associated with the development of hepatic steatosis
Summary
Liver is an essential organ in carrying out critical metabolic functions, ranging from metabolism of nutrients, synthesis of glucose and lipids, to detoxification of drugs and xenobiotics. Disruptions of liver metabolic functions may lead to a broad range of liver diseases such as metabolic syndrome, obesity and cancer [1,2,3,4]. Through a comprehensive analysis of the 14 types of human BMPs, we have demonstrated that several osteogenic BMPs, such as BMP2, 4, 6, 7 and 9, are potent factors to drive adipogenic differentiation of mesenchymal stem cells [10,11,12,13]. The effect of BMPs on lipogenesis, metabolism and energy expenditure has been mostly investigated in adipogenic progenitors and adipose tissue. The direct impact of BMP signaling on hepatic metabolism, especially on glucose and lipid production, as well as possible association of BMP signaling with NAFLD, remains to be fully understood
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