Uncarboxylated Osteocalcin Inhibits De Novo Lipogenesis and Promotes Fatty Acid Oxidation via SIRT1 to Alleviate Hepatocyte Lipid Accumulation

Abstract

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by the hepatic lipids accumulation resulting from genetic susceptibility and metabolic dysfunction. Uncarboxylated osteocalcin (GluOC) is a protein that is synthesized by osteoblasts which performs a vital function in the management of energy balance. Previous studies have shown that GluOC is beneficial for lipid and glucose metabolism in KKAy mice induced fatty liver. GluOC effectively ameliorates hyperglycemia, fatty liver, and hyperlipidemia. Furthermore, it regulates stearyl-coenzyme A desaturase 1 (SCD1) expression through AMP-activated protein kinase (AMPK), which alleviates hepatocyte lipid accumulation. However, the underlying mechanisms by which GluOC alleviates hepatocyte lipid accumulation need further elucidation. Methods In this study, the NCTC 1469 cells induced by oleic acid (OA) and palmitic acid (PA) were used in the establishment of the NAFLD cell model. Triglyceride (TG) kits and BODIPY 493/503 staining were employed to measure the levels of hepatocyte lipid accumulation. Immunoprecipitation, western blotting, and real-time PCR analyzed the expression of protein and mRNA in the fatty acid oxidation (FAO) and de novo lipogenesis (DNL) pathways. Results The results indicated that increasing concentrations of GluOC resulted in reduced intracellular lipid accumulation and triglyceride levels. GluOC promoted sirtuin1 (SIRT1) expression, inhibited acetyl-CoA carboxylase (ACC) and fatty acid synthetase (FASN) expression, promoted medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) expression. In addition, GluOC activated AMPK phosphorylation and peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α) deacetylation. si-SIRT1 attenuated the above effects of GluOC, resulting in hepatocyte lipid accumulation. Conclusion GluOC inhibited DNL via SIRT1-AMPK and promoted FAO via SIRT1-PGC-1α to alleviate lipid accumulation in hepatocytes. This provides new insights for further research in NAFLD.