Analysis of SIK3, newly regulator of glucose, lipid, cholesterol, and bile acid

SIK3-KO小鼠没有发胖，但引起肝功能障碍。为了开发抗肥胖药物，本研究分析了SIK3的功能。SIK3-KO小鼠对胆汁酸高度敏感，高胆汁酸水平可引起严重的肝功能障碍。通过对基因表达水平的分析，发现SIK-KO小鼠失去了对胆固醇和胆汁酸相关基因的表达调控。提示SIK3是胆固醇和胆汁酸稳态的主要调控因子。通过质谱分析磷酸化蛋白，发现了SIK3的两个候选靶蛋白。由于SIK3-KO与野生型之间的脂肪酸组成没有差异，因此提示脂肪酸与能量反流无关。

SIK3-KO mice do not get fat, but were caused liver dysfunction. In order to develop the anti-obesity drug, in this study, a function of SIK3 was analyzed. SIK3-KO mice were high sensitive to bile acid, and the high bile acid level induced serious liver dysfunction. By analysis of gene expression level, it was found that SIK-KO mice lost the regulation of expression of gene related to cholesterol and bile acid responding a diet.It was suggested that SIK3 was master regulator of cholesterol and bile acid homeostasis. By mass spectrometry analysis of phosphorylatedproteins, two candidate target proteins of SIK3 were found. Since there was no difference in the fatty acid composition between SIK3-KO and wild type, it was suggested that fatty acid do not relate to energy reflux.