Elucidation of the physiological role of fatty acid elongase Elovl6 in liver and development of new strategy for the treatment of metabolic disease

• Project/Area Number: 21689025
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: University of Tsukuba
• Principal Investigator: MATSUZAKA Takashi 筑波大学, 医学医療系, 准教授 (70400679)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥24,830,000 (Direct Cost: ¥19,100,000、Indirect Cost: ¥5,730,000); Fiscal Year 2011: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2010: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2009: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 脂肪酸 / エネルギー代謝 / インスリン感受性 / 肥満 / メタボリックシンドローム / Elovl6 / 生活習慣病 / 肝臓 / 脂肪酸合成 / 脂肪酸組成

Research Abstract

Elovl6 is a microsomal enzyme involved in the elongation of saturated and monounsaturated fatty acids with 12, 14, and 16 carbons. In this research, I generated liver-specific Elovl6 deficient mice (LKO), and aimed to elucidate the physiological role of Elovl6 in the liver and identify the lipid factor which control energy metabolismand insulin sensitivity. LKO mice reduce stearate and oleate levels, and increases palmitate and palmitoleate levels in the liver. In contrast to Elovl6^<-/->. mice, LKO mice were not protected against HFHS diet. However, high sucrose diet-feeding in LKO mice caused higher insulin sensitivity than those of flox mice. These results suggest that products of the Elovl6 reaction through de novo lipogenesis regulates hepatic insulin sensitivity, but Elovl6 inhibition in extrahepatic tissue is required to protect mice from HFHS-induced insulin resistance.

Research Products

• [Journal Article] TFE3 reg ulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice (2012)
  • Author(s): Iwasaki H, Naka A, Iida KT, Nakagawa Y, Matsuzaka T, Ishii KA, Kobayashi K, Takahashi A, Yatoh S, Yahagi N, Sone H, Suzuki H, Yamada N, Shimano H
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302(7)
  • Peer Reviewed
• [Journal Article] Dicer has a crucial role in the early stage of adipocyte differentiation, but not in lipid synthesis, in 3T3-L1 cells (2012)
  • Author(s): Fujimoto Y, Nakagawa Y, Matsuzaka T, Shimano H, et al.
  • Journal Title: Biochem Biophys Res Commun Volume: (in press)
  • Peer Reviewed
• [Journal Article] TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice (2012)
  • Author(s): Iwasaki H, Naka A, Matsuzaka T, Shimano H, et al.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302(7)
  • Peer Reviewed
• [Journal Article] Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Saito R, Matsuzaka T, Karasawa T, Sekiya M, Okada N, Igarashi M, Matsumori R, Ishii K, Nakagawa Y, Iwasaki H, Kobayashi K, Yatoh S, Takahashi A, Sone H, Suzuki H, Yahagi N, Yamada N, Shimano H
  • Journal Title: ArteriosclerThromb Vasc Biol Volume: 31(9) Pages: 1973-9
  • Peer Reviewed
• [Journal Article] In hibition of ubiquitin ligase F-box and WD re peat domain-containing 7α (Fbw7α) causes he patosteatosis through Kruppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice (2011)
  • Author(s): Kumadaki S, Karasawa T, Matsuzaka T, Ema M, Nakagawa Y, Nakakuki M, Saito R, Yahagi N, Iwasaki H, Sone H, Takekoshi K, Yatoh S, Kobayashi K, Takahashi A, Suzuki H, Takahashi S, Yamada N, Shimano H
  • Journal Title: J Biol Chem Volume: 286(47) Pages: 40835-46
  • Peer Reviewed
• [Journal Article] Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Karasawa T, Takahashi A, Saito R, Sekiya M, Igarashi M, Iwasaki H, Miyahara S, Koyasu S, Nakagawa Y, Ishii K, Matsuzaka T, Kobayashi K, Yahagi N, Takekoshi K, Sone H, Yatoh S, Suzuki H, Yamada N, Shimano H
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(8) Pages: 1788-95
  • Peer Reviewed
• [Journal Article] Macrophage Elov16 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Saito R, Matsuzaka T, Yamada N, Shimano H, et al.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(9) Pages: 1973-9
  • Peer Reviewed
• [Journal Article] Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7a (Fbw7α) causes hepatosteatosis through Kruppel-like factor 5 (KLF5)/p eroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice (2011)
  • Author(s): Kumadaki S, Matsuzaka T, Yamada N, Shimano H, et al.
  • Journal Title: J Biol Chem Volume: 286(47) Pages: 40835-46
  • Peer Reviewed
• [Journal Article] Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin. (2010)
  • Author(s): Yamamoto T, Watanabe K, Inoue N, Nakagawa Y, Ishigaki N, Matsuzaka T, Takeuchi Y, Kobayashi K, Yatoh S, Takahashi A, Suzuki H, Yahagi N, Gotoda T, Yamada N, Shimano H.
  • Journal Title: J Lipid Res. Volume: 51 Pages: 1859-70
  • Peer Reviewed
• [Journal Article] Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. (2010)
  • Author(s): Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T, Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K, Osuga J, Gotoda T, Ishibashi S, Itaka K, Kataoka K, Nagai R, Yamada N, Kadowaki T, Shimano H.
  • Journal Title: J Biol Chem. Volume: 285 Pages: 11681-91
  • Peer Reviewed
• [Journal Article] Protein kinase Cbeta mediates hepatic induction of sterol regulatory element-binding protein-1c by insulin (2010)
  • Author(s): Yamamoto T, Watanabe K, Inoue N, Nakagawa Y, Ishigaki N, Matsuzaka T, Takeuchi Y, Kobayashi K, Yatoh S, Takahashi A, Suzuki H, Yahagi N, Gotoda T, Yamada N, Shimano H.
  • Journal Title: J Lipid Res. Feb 23.(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit (2010)
  • Author(s): Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T, Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K, Osuga J, Gotoda T, Ishibashi S, Itaka K, Kataoka K, Nagai R, Yamada N, Kadowaki T, Shimano H.
  • Journal Title: J Biol Chem. 285(15) Pages: 11681-11691
  • Peer Reviewed
• [Journal Article] The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARalpha (2010)
  • Author(s): Danno H, Ishii KA, Nakagawa Y, Mikami M, Yamamoto T, Yabe S, Furusawa M, Kumadaki S, Watanabe K, Shimizu H, Matsuzaka T, Kobayashi K, Takahashi A, Yatoh S, Suzuki H, Yamada N, Shimano H.
  • Journal Title: Biochem Biophys Res Commun. 391(2) Pages: 1222-1227
  • Peer Reviewed
• [Journal Article] Elovl6 : a new player in fatty acid metabolism and insulin sensitivity (2009)
  • Author(s): Matsuzaka T, Shimano H.
  • Journal Title: J Mol Med. 87(4) Pages: 379-384
  • Peer Reviewed
• [Presentation] "PEGylated and quatemized polyamine nanogel", a brand-new bile acid sequestrant, ameliorates lipoprotein profiles and reduces atherosclerosis in low-density-lipoprotein receptor deficient and apolipoprotein E deficient mice (2012)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al.
  • Organizer: 第76回日本循環器病学会
  • Place of Presentation: 福岡国際会議場(福岡市)
  • Year and Date: 2012-03-17
• [Presentation] A novel bile salt sequestering agent_PEGylated and quaternized polyamine nanogel reduces VLDLand LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第84回米国心臓協会学術集会(AHA Scientific Sessions 2011)
  • Year and Date: 2011-11-15
• [Presentation] A novel bile salt sequestering agent_"PEGylated and quaternized polya mine nanogel" reduces VLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al.
  • Organizer: 第84回米国心臓協会学術集会(AHA Scientific Sessions 2011)
  • Place of Presentation: アメリカ(フロリダ)
  • Year and Date: 2011-11-15
• [Presentation] PEGylatedand quaternized polyamine nanogel a novel bile salt sequestering agent, ameliorates dyslipidmia through reduction of VLDL and LDL cholesterol, and induction of HDL cholesterol (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第43回日本動脈硬化学会学術集会
  • Year and Date: 2011-07-16
• [Presentation] "PEGylated and quaternized polyamine nanogel" a novel bile salt sequestering agent, ameliorates dyslipidmia through reduction of VLDL and LDL cholesterol, and induction of HDL cholesterol (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al.
  • Organizer: 第43回日本動脈硬化学会学術集会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2011-07-16
• [Presentation] A novel bile salt sequestering agent PEGylated and quaternized polyamine nanogel reduces VLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Haruna Shinozaki, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第34回日本分子生物学会年会
• [Presentation] A novel bile salt sequestering agent PEGylated and quaternized polyamine nanogel reduces VLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Haruna Shinozaki, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
• [Presentation] Nutritional regulation and physiological role of ELOVL family member 5(Elovl5) (2010)
  • Author(s): Takashi Matsuzaka, Saori Koyasu, Yoshimi Nakagawa, Tomotaka Yokoo, Nobuhiro Yamada, Hitoshi Shimano
  • Organizer: 14^<th> International Congress of Endocrinology
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-03-30
• [Presentation] 糖尿病における脂肪酸組成コントロールの重要性と長鎖脂肪酸伸長酵素Elovl6の役割 (2009)
  • Author(s): 松坂賢、山田信博、島野仁
  • Organizer: 第52回 日本糖尿病学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2009-05-23
• [Presentation] 非アルコール性脂肪性肝炎の発症・進展における脂肪酸伸長酵素Elovl6の役割 (2009)
  • Author(s): 松坂賢、島野仁、渥美綾香、山田信博
  • Organizer: 第82回 日本内分泌学会学術集会
  • Place of Presentation: 群馬県民会館
  • Year and Date: 2009-04-24
• [Book] Annual Review糖尿病・代謝・内分泌 脂肪酸伸長酵素と肥満・インスリン抵抗性 (2010)
  • Author(s): 松坂賢、島野仁
  • Total Pages: 7
  • Publisher: 中外医学社
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/
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  • URL: http://www.md.tsukuba.ac.jp/clinical-med/endocrinology/research/