SIK3 is a new regulator of lipid homeostasis in the mouse liver

Abstract

A life free from obesity is very appealing in today's modern society. Here, we report a new molecule that links cholesterol‐bile acid homeostasis with energy storage capacity. Salt‐inducible kinase 3 (SIK3), an AMP‐activated protein kinase‐related kinase, is induced in the murine liver after consumption of a diet rich in fat, sucrose, and cholesterol. Sik3−/− mice have a malnourished phenotype (i.e., lipodystrophy, hypolipidemia, and hypoglycemia) accompanied by cholestasis and cholelithiasis. These biliary disorders are correlated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoid X receptor (RXR) plays a role in cholesterol and bile acid homeostasis, while ALDH1a, which produces the RXR ligand 9‐cis‐retinoic acid, is expressed at low levels in Sik3‐KO mice. The disorders of lipid metabolism in Sik3−/− mice are ameliorated by the treatment with 9‐cis‐retinoic acid. Moreover, the administration of adenoviruses expressing human SIK3 into Sik3−/− mice restores gene expression profiles responding to nutritional stresses, including the Aldh1a gene. In conclusion, SIK3 is a novel energy regulator that increases nutritional storage by facilitating the clearance of cholesterol and bile acids while leading to obesity.