2011 Fiscal Year Final Research Report
SIK acts as the third cholesterol sensor
| Project/Area Number |
22659176
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Metabolomics
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| Research Institution | 独立行政法人医薬基盤研究所 |
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Principal Investigator |
TAKEMORI Hiroshi 独立行政法人医薬基盤研究所, 創薬基盤研究部, プロジェクトリーダー (90273672)
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| Project Period (FY) |
2010 – 2011
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| Keywords | SIK / CRTC1 / 糖代謝 / 脂質代謝 / コレステロール / 胆汁酸 |
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| Research 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.
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Research Products
(20 results)
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[Journal Article] Involvement of SIK3 in glucose and lipid homeostasis in mice2012
Author(s)
Uebi T, Itoh Y, Hatano O, Kumagai A, Sanosaka M, Sasaki T, Sasagawa S, Doi J, Tatsumi K, Mitamura K, Morii M, Aozasa K, Kawamura T, Okumura M, Nakae J, Takikawa H, Fukusato T, Koura M, Nish M, Hamsten A, Silveira A, Bertorello AM, Kitagawa K, Nagaoka Y, Kawahara H, Tomonaga T, Naka T, Ikegawa S, Tsumaki N, Matsuda J, Takemori H
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Journal Title
PLoS ONE
Volume: 7
Pages: e37803
DOI
Peer Reviewed
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[Journal Article] Novel repressor regulates insulin sensitivity through interaction with Foxol2012
Author(s)
Nakae J, Cao Y, Hakuno F, Takemori H, Kawano Y, Sekioka R, Abe T, Kiyonari H, Tanaka T, Sakai J, Takahashi SI, Itoh H
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Journal Title
EMBO J
Volume: 31
Pages: 2275-2295
DOI
Peer Reviewed
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[Journal Article] Carbohydrate metabolism is perturbed in peroxisome deficient hepatocytes due to mitochondrial dysfunction, AMP activated protein kinase(AMPK) activation and peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α) suppression.2011
Author(s)
Peeters A, Fraisl P, Berg S, Themaat E, Kampen A, Rider MH, Takemori H, Dijk K, Veldhoven P, Carmeliet P, Baes M
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Journal Title
J. Biol. Chem.
Volume: 286
Pages: 42162-79
DOI
Peer Reviewed
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[Journal Article] Salt-inducible kinase 1 influences Na+, K+-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure.2011
Author(s)
Popov S, Silveira A, Wagsater D, Takemori H, Oguro R, Matsumoto S, Sugimoto K, Kamide K, Hirose T, Satoh M, Metoki H, Kikuya M, Ohkubo T, Katsuya T, Rakugi H, Imai Y, Sanchez F, Leosdottir M, Syvanen AC, Hamsten A, Melander O, Bertorello AM.
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Journal Title
J Hypertens
Volume: 29
Pages: 2395-2403
DOI
Peer Reviewed
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[Journal Article] A potent inhibitor of SIK2, 3, 3', 7-trihydroxy-4'-methoxyflavon(4'-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells2011
Author(s)
Kumagai A, Horike N, Satoh Y, Uebi T, Sasaki T, Itoh Y, Hirata Y, Uchio-Yamada K, Kitagawa K, Uesato S, Kawahara H, Takemori H, Nagaoka Y
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Journal Title
PLoS ONE
Volume: 6
Pages: e26148
DOI
Peer Reviewed
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