Zhang Mingliang, Nie Xiaomin, Yuan Yeqing, Wang Yansu, Ma Xiaojing, Yin Jun, Bao Yuqian
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China.
Int J Endocrinol. 2021 Jan 15;2021:9178616. doi: 10.1155/2021/9178616. eCollection 2021.
Osteocalcin is a bone-derived hormone that plays an important role in the crosstalk between bone and energy metabolism. Previous studies have found that treatment with uncarboxylated osteocalcin can protect mice from high-fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the potential mechanisms remain unclear. Although the G protein-coupled receptor family C group 6 subtype A (GPRC6A) is the putative receptor of osteocalcin, there is no direct evidence showing that GPRC6A mediates the effects of uncarboxylated osteocalcin in alleviating NAFLD in mice. We aimed to figure out this using liver-specific GPRC6A knockout (GPRC6A) mice. Consistent with previous studies, uncarboxylated osteocalcin significantly protected high-fat diet-fed wild-type mice from obesity and NAFLD, while it did not protect high-fat diet-fed GPRC6A mice from NAFLD. Differential mRNA expression of lipogenesis and lipolysis between GPRC6A mice and control mice revealed that GPRC6A mediated the effects of osteocalcin in alleviating NAFLD through inhibiting lipid synthesis and promoting lipolysis. In conclusion, this study found that uncarboxylated osteocalcin alleviates NAFLD in mice through the GPRC6A signaling pathway. Our study suggests that liver GPRC6A may be a potential target for treating NAFLD.
骨钙素是一种骨源性激素，在骨与能量代谢的相互作用中发挥重要作用。以往研究发现，用未羧化骨钙素治疗可保护小鼠免受高脂饮食诱导的非酒精性脂肪性肝病（NAFLD）。然而，其潜在机制仍不清楚。尽管G蛋白偶联受体C族第6亚组A类（GPRC6A）是骨钙素的假定受体，但尚无直接证据表明GPRC6A介导未羧化骨钙素对减轻小鼠NAFLD的作用。我们旨在通过肝脏特异性GPRC6A基因敲除（GPRC6A）小鼠来弄清楚这一点。与以往研究一致，未羧化骨钙素显著保护高脂饮食喂养的野生型小鼠免受肥胖和NAFLD影响，而它并未保护高脂饮食喂养的GPRC6A小鼠免受NAFLD影响。GPRC6A小鼠与对照小鼠之间脂肪生成和脂肪分解的mRNA表达差异表明，GPRC6A通过抑制脂质合成和促进脂肪分解介导骨钙素对减轻NAFLD的作用。总之，本研究发现未羧化骨钙素通过GPRC6A信号通路减轻小鼠NAFLD。我们的研究表明肝脏GPRC6A可能是治疗NAFLD的潜在靶点。
