Abstract
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.
Highlights
Cholesterol has diverse functions in eukaryotes, e.g., as a cell membrane component and a source of hormones and bile acid (BA)
We found that Sik22/2 mice show resistance to brain ischemia [18]; Sik22/2 mice are apparently normal in terms of body weight regulation [19]
To reevaluate individual Salt-inducible kinase (SIK) isoforms in the regulation of nutrient metabolism, normal C57BL/6J mice were fed with a variety of diets, and we examined their mRNA levels were examined
Summary
Cholesterol has diverse functions in eukaryotes, e.g., as a cell membrane component and a source of hormones and bile acid (BA). The liver X receptor (LXR) is a nuclear receptor that binds to target DNA elements by forming a heterodimer complex with the retinoid X receptor (RXR) [2,3]. LXR up-regulates hepatic fatty acid (FA) synthesis by inducing the expression of sterol regulatory element-binding protein 1c (SREBP1c) [4]. The farnesoid X receptor (FXR) senses BA as its ligand, forms a complex with RXR, and up-regulates gene expression to lower the level of BA in the liver [5] by inducing the bile salt export pump (BSEP) and small heterodimer partner (SHP), which suppresses Cyp7a expression [6]. A reduction of the BA pool by the activation of FXR induces obesity and hyperglycemia [8], suggesting that cholesterol-BA homeostasis is important for lipid and glucose metabolism
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