Involvement of SIK3 in glucose and lipid homeostasis in mice.
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.
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
Tatsuya
T
Uebi
Yumi
Y
Itoh
Osamu
O
Hatano
Ayako
A
Kumagai
Masato
M
Sanosaka
Tsutomu
T
Sasaki
Satoru
S
Sasagawa
Junko
J
Doi
Keita
K
Tatsumi
Kuniko
K
Mitamura
Eiichi
E
Morii
Katsuyuki
K
Aozasa
Tomohiro
T
Kawamura
Meinoshin
M
Okumura
Jun
J
Nakae
Hajime
H
Takikawa
Toshio
T
Fukusato
Minako
M
Koura
Mayumi
M
Nish
Anders
A
Hamsten
Angela
A
Silveira
Alejandro M
AM
Bertorello
Kazuo
K
Kitagawa
Yasuo
Y
Nagaoka
Hidehisa
H
Kawahara
Takeshi
T
Tomonaga
Tetsuji
T
Naka
Shigeo
S
Ikegawa
Noriyuki
N
Tsumaki
Junichiro
J
Matsuda
Hiroshi
H
Takemori
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D059305:Diet, High-Fat; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D001647:Bile Acids and Salts; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; C571369:SIK3 protein, mouse; D019826:Cholic Acid; D005947:Glucose