SIK acts as the third cholesterol sensor

• Project/Area Number: 22659176
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: 独立行政法人医薬基盤研究所
• 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)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,260,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: SIK / CRTC1 / 糖代謝 / 脂質代謝 / コレステロール / 胆汁酸 / 肝 / 転写因子 / CREB / 脳 / 生体エネルギー / LXR / FXR / 肝臟 / 脂肪

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.

Research Products

• [Journal Article] Involvement of SIK3 in glucose and lipid homeostasis in mice (2012)
  • 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
  • Journal Title: PLoS ONE Volume: 7
  • Peer Reviewed
• [Journal Article] Increases in intracellular sodium activate transcription and gene expression via the salt-inducible kinase 1 network in an atrial myocyte cell line (2012)
  • Author(s): Popov S, Venetsanou K, Chedrese PJ, Pinto V, Takemori H, Franco-Cereceda A, Eriksson P, Mochizuki N, Soares-da-Silva P, Bertorello AM
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Novel repressor regulates insulin sensitivity through interaction with Foxol (2012)
  • 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
  • Journal Title: EMBO J Volume: 31 Pages: 2275-2295
  • Peer Reviewed
• [Journal Article] SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice (2012)
  • Author(s): Sasagawa S, Takemori H, Uebi T, Ikegami D, Hiramatsu K, Ikegawa S, Yoshikawa H, Tsumaki N
  • Journal Title: Development Volume: 139 Pages: 1153-63
  • Peer Reviewed
• [Journal Article] Cocaine induces the expression of MEF2C transcription factor in rat striatum through activation of SIK1 and phosphorylation of the histone deacetylase HDAC5. (2012)
  • Author(s): Dietrich JB, Takemori H, Grosch-Dirrig S, Bertorello A, Zwiller J.
  • Journal Title: Synapse Volume: 66 Pages: 61-70
  • Peer Reviewed
• [Journal Article] Involvement of SIK3 in glucose and lipid homeostasis in mice (2012)
  • 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, Silveiral A, Bertorellol AM, Kitagawa K, Nagaoka Y, Kawahara H, Tomonaga T, Naka T, Ikegawa S, Tsumaki N, Matsuda J, Takemori H
  • Journal Title: PLoS ONE Volume: e7(in press)
  • Peer Reviewed
• [Journal Article] Salt inducible kinase is involved in the regulation of corticotropin releasing hormone transcription in hypothalamic neurons in rats. (2011)
  • Author(s): Liu Y, Poon V, Sanchez-Watts G, Watts AG, Takemori H, Aguilera G
  • Journal Title: Endocrinology Volume: 153 Pages: 223-33
  • Peer Reviewed
• [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
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 42162-79
  • Peer Reviewed
• [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.
  • Journal Title: J Hypertens Volume: 29 Pages: 2395-2403
  • Peer Reviewed
• [Journal Article] A potent inhibitor of SIK2, 3, 3', 7-trihydroxy-4'-methoxyflavon(4'-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells (2011)
  • 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
  • Journal Title: PLoS ONE Volume: 6
  • Peer Reviewed
• [Journal Article] Salt-inducible kinase 1 is present in lung alveolar epithelial cells and regulates active sodium transport (2011)
  • Author(s): Eneling K, Chen J, Welch LC, Takemori H, Sznajder JI, Bertorello AM.
  • Journal Title: Biochem Biophys Res Commun Volume: 409 Pages: 28-33
  • Peer Reviewed
• [Journal Article] SIK2 is a new key regulator for neuronal survival after ischemia through TORC1-CREB (2011)
  • Author(s): Sasaki T, Takemori H, Yagita Y, Terasaki Y, Uebi T, Horike N, Takagi H, Susumu T, Teraoka H, Kusano K, Hatano O, Oyama N, Sugiyama Y, Sakoda S, Kitagawa K
  • Journal Title: Neuron Volume: 69 Pages: 106-119
  • Peer Reviewed
• [Journal Article] Downregulation of SIK2 expression promotes the melanogenic program in mice (2010)
  • Author(s): Horike N, Kumagai A, Shimono Y, Onishi T, Itoh Y, Sasaki T, Kitagawa K, Hatano O, Takagi H, Susumu T, Teraoka H, Kusano K, Nagaoka Y, Kawahara H, Takemori H.
  • Journal Title: Pigment Cell Melanoma Res Volume: 23 Pages: 809-819
  • Peer Reviewed
• [Journal Article] Phosphorylation of the CREB-specific coactivator TORC2 at Ser307 regulates its intracellular localization in COS-7 cells and in the mouse liver (2010)
  • Author(s): Uebi T, Tamura M, Horike N, Hashimoto YK, Takemori H.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 299
  • Peer Reviewed
• [Presentation] SIK3はコレステロール-胆汁酸代謝の制御因子である (2011)
  • Author(s): 上尾達也,伊東裕美,熊谷彩子,竹森洋
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] SIK3はコレステロール-胆汁酸代謝の制御因子である (2011)
  • Author(s): 上尾達也、伊東裕美、熊谷彩子、竹森洋
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2011-12-16
• [Presentation] 塩誘導性キナーゼSIK3-KOマウスに観察される胆汁うっ滞 (2011)
  • Author(s): 竹森洋、上尾達也、伊東祐美、熊谷彩子、佐野坂真人
  • Organizer: 第33回胆汁酸研究会
  • Place of Presentation: 大阪
  • Year and Date: 2011-11-19
• [Presentation] 塩誘導性キナーゼSIK3-KOマウスに観察される胆汁うっ滞 (2011)
  • Author(s): 竹森洋、上尾達也、伊東祐美、熊谷彩子、佐野坂真人
  • Organizer: 第33回胆汁酸研究会
  • Place of Presentation: 大阪ガーデンパレス(大阪)
  • Year and Date: 2011-11-19
• [Presentation] 塩誘導性キナーゼSIK3はコレステロールのクリアランスを制御する (2011)
  • Author(s): 伊東祐美、上尾達也、熊谷彩子、竹森洋、土居純子
  • Organizer: 第50回日本栄養食糧学会・近畿支部大会
  • Place of Presentation: 奈良
  • Year and Date: 2011-10-15
• [Presentation] 塩誘導性キナーゼSIK3はコレステロールのクリアランスを制御する (2011)
  • Author(s): 伊東祐美、上尾達也、熊谷彩子、竹森洋、土居純子
  • Organizer: 第50回日本栄養食糧学会・近畿支部大会
  • Place of Presentation: 近畿大学(奈良)
  • Year and Date: 2011-10-15
• [Presentation] 塩誘導性キナーゼSIK3はコレステロールのクリアランスを制御する (2011)
  • Author(s): 伊東祐美、上尾達也、熊谷彩子、竹森洋
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [Presentation] 塩誘導性キナーゼSIK3はコレステロールのクリアランスを制御する (2011)
  • Author(s): 伊東祐美、上尾達也、熊谷彩子、竹森洋
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2011-09-23
• [Presentation] PACAPはNMDAレセプター活性化によるカルシニューリン-TORC1-CREB経路を介してBDNF遺伝子発現を誘導する (2011)
  • Author(s): 福地守、桑名由紀、竹森洋、田渕明子、津田正明
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-17
• [Presentation] 脳虚血後SIK2-TORC1-CREB経路の動態 (2011)
  • Author(s): 佐々木勉、竹森洋、寺崎泰和、杉山幸生、大山直紀、川村美貴、八木田佳樹、北川一夫
  • Organizer: STROK 2011
  • Place of Presentation: 京都
  • Year and Date: 2011-08-01
• [Presentation] 脳虚血後SIK2-TORC1-CREB経路の動態 (2011)
  • Author(s): 佐々木勉、竹森洋、寺崎泰和、杉山幸生、大山直紀、川村美貴、八木田佳樹、北川一夫
  • Organizer: STROKE 2011
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2011-08-01
• [Presentation] トキワムシゴケのアセトン抽出物によるメラニン生成抑制機構の解明 (2011)
  • Author(s): 下野優子,竹森洋,長岡康夫,河原秀久,山原年
  • Organizer: 第10回日本地衣学会
  • Place of Presentation: 神戸
  • Year and Date: 2011-07-09
• [Presentation] A new melanogenesis inhibitor in metabolites of white fruticose lichen Thamnolia subuliformis (2010)
  • Author(s): Shimono Y, Kumagai A, Nagaoka Y, Takemori H, Kawahara H
  • Organizer: Pacifichem
  • Place of Presentation: Hawaii
  • Year and Date: 2010-12-15
• [Remarks]
  • URL: http://www.nibio.go.jp/part/project/metabolism_disease/
• [Patent(Industrial Property Rights)] PPARd活性化剤およびPPARd活性化剤の製造方法 (2011)
  • Inventor(s): 河原秀久、長岡康夫、竹森洋、小出芳栄
  • Industrial Property Rights Holder: 学校法人関西大学、独立行政法人医薬基盤研究所、有限会社一栄
  • Filing Date: 2011-11-26
• [Patent(Industrial Property Rights)] 軟骨疾患治療薬のスクリーニング方法および軟骨疾患治療用改変細胞 (2011)
  • Inventor(s): 妻木範行、竹森洋
  • Industrial Property Rights Holder: 国立大学法人大阪大学、独立行政法人医薬基盤研究所
  • Filing Date: 2011-05-31
• [Patent(Industrial Property Rights)] 軟骨疾患治療薬のスクリーニング方法および軟骨疾患治療用改変細胞 (2011)
  • Inventor(s): 妻木範行、竹森洋
  • Industrial Property Rights Holder: 国立大学法人大阪大学、独立行政法人医薬基盤研究所
  • Industrial Property Number: 2011-121788
  • Filing Date: 2011-05-31
• [Patent(Industrial Property Rights)] メラニン産生促進剤 (2010)
  • Inventor(s): 長岡康夫、熊谷彩子、堀家なな緒、竹森洋、堀部一平、小畑勝義
  • Industrial Property Rights Holder: 関西大学
  • Industrial Property Number: 2010-146931
  • Filing Date: 2010-06-28