Myeliod specific inhibition of cholesterol synthesis ameliorates insulin sensitivity and hepatic steatosis.

• Project/Area Number: 26870533
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology; Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: NAGASHIMA SHUICHI 自治医科大学, 医学部, 講師 (30406136)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HMG-CoA還元酵素 / インスリン抵抗性 / 糖尿病 / マクロファージ / スタチン / 脂肪肝 / 炎症 / クッパー細胞 / NAFLD

Outline of Final Research Achievements

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis. HMGCR inhibitors (statins) have been reported to exert cholesterol-lowering independent regression of atherosclerotic plaque by decreasing macrophage accumulation and the inflammatory process in the lesion. We hypothesized that genetically myeloid-specific inhibition of HMGCR would decrease adipose tissue inflammation. As expected, diet-induced obese mice with myeloid-specific HMGCR KO had lesser macrophage accumulation and expression of inflammatory cytokines in the adipose tissue compared with control mice. In insulin tolerance test, obese KO mice demonstrated improved systemic insulin sensitivity with enhanced insulin signaling in the adipose tissue. Moreover, in obese KO mice hepatic steatosis was improved without the change of hepatic inflammatory characteristics. Our data indicate the pivotal role of HMGCR in innate immune cells in regulating systemic insulin sensitivity and hepatic steatosis.

Research Products

• [Journal Article] Possible involvement of PCSK9 overproduction in hyperlipoproteinemia associated with hepatocellular carcinoma: A case report. (2016)
  • Author(s): Nagashima S, Morishima K, Okamoto H, Ishibashi S
  • Journal Title: J Clin Lipidol Volume: 10 Issue: 4 Pages: 1045-1049
  • DOI: 10.1016/j.jacl.2016.05.004
  • Peer Reviewed / Open Access
• [Journal Article] Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver. (2015)
  • Author(s): Nagashima S, Yagyu H, Tozawa R, Tazoe F, Takahashi M, Kitamine T, Yamamuro D, Sakai K, Sekiya M, Okazaki H, Osuga J, Honda A, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 56 Issue: 5 Pages: 998-1005
  • DOI: 10.1194/jlr.m057406
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Successful pregnancy outcomes in a patient with type A insulin resistance syndrome (2015)
  • Author(s): Enkhtuvshin B, Nagashima S, Saito N, Wakabayashi T, Ando A, Takahashi M, Sakai K, Yamamuro D, Nagasaka S, Tamemoto H, Ishibashi S.
  • Journal Title: Diabet Med Volume: 32 Issue: 6
  • DOI: 10.1111/dme.12659
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of the length of the first β strand in insulin receptor kinase activity (2015)
  • Author(s): Enkhtuvshin B, Tamemoto H, Nagashima S, Tumenbayar B, Sakai K, Osuga J, Takahashi M, Tominaga S, Ishibashi S.
  • Journal Title: Jichi Medical University journal Volume: 38 Pages: 1-8
  • NAID: 120006408287
  • Peer Reviewed
• [Journal Article] An adverse pregnancy-associated outcome due to overlooked primary aldosteronism. (2014)
  • Author(s): Eguchi K, Hoshide S, Nagashima S, Maekawa T, Sasano H, Kario K.
  • Journal Title: Intern Med Volume: 53 Pages: 2499-2504
  • Peer Reviewed / Open Access
• [Journal Article] Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages. (2014)
  • Author(s): Sekiya M, Yamamuro D, Ohshiro T, Honda A, Takahashi M, Kumagai M, Sakai K, Nagashima S, Tomoda H, Igarashi M, Okazaki H, Yagyu H, Osuga J, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 55 Issue: 10 Pages: 2082-2092
  • DOI: 10.1194/jlr.m050864
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Critical role of neutral cholesteryl ester hydrolase 1 in cholesteryl ester hydrolysis in murine macrophages (2014)
  • Author(s): Sakai K, Igarashi M, Yamamuro D, Ohshiro T, Nagashima S, Takahashi M, Enkhtuvshin B, Sekiya M, Okazaki H, Osuga J, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 55 Issue: 10 Pages: 2033-2040
  • DOI: 10.1194/jlr.m047787
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 膵β細胞特異的HMG-CoA還元酵素欠損マウスにおける糖尿病発症機序の解析 (2017)
  • Author(s): 武井祥子、永島秀一他
  • Organizer: 日本糖尿病学会年次学術集会
• [Presentation] 肥満脂肪組織慢性炎症誘導におけるマクロファージ由来リポ蛋白リパーゼの意義 (2017)
  • Author(s): 高橋学、野牛宏晃、永島秀一他
  • Organizer: 日本動脈硬化学会総会
• [Presentation] 肝臓特異的スクアレン合成酵損欠損マウスの血中・肝脂質代謝と肝機能の検討 (2014)
  • Author(s): 永島秀一, 野牛宏晃, 兎澤隆一, 田副文子, 高橋学, 坂井謙斗, 山室大介, エンフトウシュン・ボロルマー , 関谷元博, 岡崎啓明, 大須賀淳一, 石橋俊
  • Organizer: 日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] 肝臓特異的スクアレン合成酵素欠損マウスの血中・肝脂質代謝と肝機能の検討 (2014)
  • Author(s): 永島秀一, 野牛宏晃, 兎澤隆一, 田副文子, 高橋学, 坂井謙斗, 山室大介, エンフトウシュン・ボロルマー , 関谷元博, 岡崎啓明, 大須賀淳一, 石橋俊
  • Organizer: 日本臨床分子医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-11 – 2014-04-12
• [Book] そうだったんだ！脂質異常症 (2016)
  • Author(s): 永島秀一、石橋俊
  • Total Pages: 2
  • Publisher: 文光堂
• [Book] 疾患モデルの作製と利用－脂質代謝異常と関連疾患 (2015)
  • Author(s): 永島秀一
  • Total Pages: 6
  • Publisher: 株式会社エル・アイ・シー
• [Book] Annual Review 2015 糖尿病・代謝・内分泌 (2015)
  • Author(s): 永島秀一
  • Total Pages: 6
  • Publisher: 中外医学社
• [Book] 日本医事新報 (2014)
  • Author(s): 永島秀一, 石橋俊
  • Total Pages: 1
  • Publisher: 日本医事新報社