PLoS ONE (Jan 2012)

Involvement of SIK3 in glucose and lipid homeostasis in mice.

  • Tatsuya Uebi,
  • Yumi Itoh,
  • Osamu Hatano,
  • Ayako Kumagai,
  • Masato Sanosaka,
  • Tsutomu Sasaki,
  • Satoru Sasagawa,
  • Junko Doi,
  • Keita Tatsumi,
  • Kuniko Mitamura,
  • Eiichi Morii,
  • Katsuyuki Aozasa,
  • Tomohiro Kawamura,
  • Meinoshin Okumura,
  • Jun Nakae,
  • Hajime Takikawa,
  • Toshio Fukusato,
  • Minako Koura,
  • Mayumi Nish,
  • Anders Hamsten,
  • Angela Silveira,
  • Alejandro M Bertorello,
  • Kazuo Kitagawa,
  • Yasuo Nagaoka,
  • Hidehisa Kawahara,
  • Takeshi Tomonaga,
  • Tetsuji Naka,
  • Shigeo Ikegawa,
  • Noriyuki Tsumaki,
  • Junichiro Matsuda,
  • Hiroshi Takemori

DOI
https://doi.org/10.1371/journal.pone.0037803
Journal volume & issue
Vol. 7, no. 5
p. e37803

Abstract

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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.