Elucidation of the molecular mechanism of preventing diabetes onset by the regulation of fatty acid composition and its application for the prevention and treatment of type 2 diabetes
| Project/Area Number |
18H03189
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | 脂肪酸伸長酵素 / Elovl6 / インスリン感受性 / NAFLD / 2型糖尿病 / カルジオリピン / ミトコンドリア / 肝臓 / 膵β細胞 / セラミド / ベータ細胞 / 膵臓 / 高血糖 / 糖尿病 / 脂肪酸 / 膵ベータ細胞 |
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| Outline of Final Research Achievements |
ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout mice. Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD. To define the role of Elovl6 in pancreatic beta-cell and type 2 diabetes development, we generated beta-cell-specific Elovl6 knockout mice and assessed the effects of beta-cell specific Elovl6 deletion in db/db mice. The double mutant mice had a markedly increased β-cell mass, an adaptive increase in insulin and improved glycemic control. Taken together, inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance and diabetes.
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| Academic Significance and Societal Importance of the Research Achievements |
肝臓特異的Elovl6欠損マウスの研究結果から、セラミドの脂肪酸鎖長（炭素数）の適切な制御や肝臓におけるElovl6の阻害が、脂肪肝や糖尿病の予防・治療に対する標的として有用であると考えられます。また、膵β細胞特異的Elovl6欠損マウスの研究結果は、膵β細胞におけるElovl6 の発現や活性の変化が肥満にともなう膵β細胞量の調節や代償性インスリン分泌に重要であることを示しています。これらの成果から、Elovl6 の阻害や脂肪酸の質の管理による、脂肪肝や糖尿病の新しい予防法・治療法の開発が期待されます。
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Report
(4 results)
Research Products
(29 results)
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[Journal Article] Transgenic Mice Overexpressing SREBP-1a in Male ob/ob Mice Exhibit Lipodystrophy and Exacerbate Insulin Resistance.2018
Author(s)
Ohno H, Matsuzaka T, Tang N, Sharma R, Motomura K, Shimura T, Satoh A, Han SI, Takeuchi Y, Aita Y, Iwasaki H, Yatoh S, Suzuki H, Sekiya M, Nakagawa Y, Sone H, Yahagi N, Yamada N, Higami Y, Shimano H.
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Journal Title
Endocrinology.
Volume: 159(6)
Issue: 6
Pages: 2308-2323
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Hepatocyte-specific deletion of Elovl6 enhances hepatic insulin sensitivity through suppression of C18:0-ceramide production2019
Author(s)
Takashi Matsuzaka, Kaori Motomura, Hiroshi Ohno, Rahul Sharma, Takuya Shimura, Yuta Yamamoto, Sundaram Arulmozhiraja, Takafumi Miyamoto, Motohiro Sekiya, Yoshimi Nakagawa, Akio Hayashi, Hiroaki Tokiwa, Hitoshi Shimano
Organizer
60th International Conference on the Bioscience of Lipids (ICBL)
Related Report
Int'l Joint Research
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