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

SIK 3-KO小鼠不会发胖，但会引起肝功能障碍。为了开发抗肥胖药物，本研究分析了SIK 3的功能。SIK 3-KO小鼠对胆汁酸高度敏感，高胆汁酸水平可导致严重的肝功能损害。通过基因表达水平分析发现，SIK-KO小鼠在饮食反应中失去了对胆固醇和胆汁酸相关基因表达的调控，提示SIK 3是胆固醇和胆汁酸稳态的主要调节因子。通过对磷酸化蛋白质的质谱分析，发现了两个候选的SIK 3靶蛋白，由于SIK 3-KO与野生型的脂肪酸组成没有差异，提示脂肪酸与能量回流无关。

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.