SIK acts as the third cholesterol sensor

盐诱导激酶3（SIK 3）是一种AMP激活的蛋白激酶相关激酶，在食用富含脂肪、蔗糖和胆固醇的饮食后，在小鼠肝脏中诱导。为了检测SIK 3是否可以调节肝脏中的葡萄糖和脂质代谢，我们分析了SIK 3缺陷小鼠的表型。Sik 3 ^-/->小鼠具有营养不良的表型（i.例如，脂肪营养不良、低脂血症、低血糖症和高胰岛素敏感性），伴有胆汁淤积和胆石症。低血糖和高胰岛素敏感性表型可能是由于能量储存减少，其表现为肝脏中脂肪酸合成途径组分的mRNA表达水平低。Sik 3 ^<-/->小鼠的胆道疾病与响应营养应激的基因表达程序的失调有关，并且可能由核受体调节。视黄酸在胆固醇和胆汁酸体内平衡中起作用，而产生视黄酸的ALDH 1a在Sik 3 ^<-/->小鼠中以低水平表达。Sik 3 ^<-/->小鼠中的脂质代谢紊乱通过用9-顺式-视黄酸治疗而改善。总之，SIK 3是一种新的能量调节剂，通过与类维生素A代谢偶联来调节胆固醇和胆汁酸代谢，并且可能改变小鼠能量储存的大小。

Salt-inducible kinase 3(SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3^<-/-> mice have a malnourished the phenotype(i. e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3^<-/-> mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3^<-/-> mice. Lipid metabolism disorders in Sik3^<-/-> mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice.