Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

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.

Salt-inducible Kinase 3 Signaling Is Important for the Gluconeogenic Programs in Mouse Hepatocytes

“…SIK3-KO mice display a lean phenotype, resistance to a high fat diet, and excessive hypoglycemia. Although a response to insulin and lactate-induced gluconeogenesis in SIK3-KO mice appeared to be normal under fasting conditions, gluconeogenic gene expression was extremely higher in the SIK3-KO liver than in WT mice (18). In addition to the lean phenotype (small amount of energy storage), impaired bile acid, cholesterol, and retinoid homeostasis with skeletal abnormalities in SIK3-KO mice (19) can make it difficult to determine whether enhanced gluconeogenic programs in the SIK3-KO mice liver were the results of a cell autonomous action or systemic effects.…”

“…However, in vivo, we observed that only SIK3-KO mice had dramatic phenotypes for energy metabolism (18). To confirm the indispensability of SIK3 in glucose metabolism in vivo, all SIKs KO mice with the same genetic background (C57BL/6J) were subjected to a glucose challenge after 4 h of starvation (Fig.…”

“…Information about the KO mice, SIK1-KO, SIK2-KO, and SIK3-KO are described in (13,15,18), respectively. SIK1-KO mice were mated with C57BL/6J for six generations.…”

“…Obvious abnormalities in glucose homeostasis have been found in SIK3-KO mice (18). SIK3-KO mice display a lean phenotype, resistance to a high fat diet, and excessive hypoglycemia.…”

Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate‐activated protein kinase‐related kinases and retinoid X receptor α

“…To date, 12 kinds of AMPK‐RKs have been identified through their sequence homology with the protein kinase domain of AMPK, and eight kinds of kinases have been identified as distant relatives of AMPK 25. Some of them, such as SIK1, SIK2, and SIK3, were reported to regulate lipid metabolism 26, 27, 28. From these facts, we assumed that one or more AMPK‐RKs regulate the activity by which RBV suppresses lipogenesis.…”