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

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H03189
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Matsuzaka Takashi 筑波大学, 医学医療系, 教授 (70400679)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 脂肪酸伸長酵素 / Elovl6 / インスリン感受性 / NAFLD / 2型糖尿病

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.

Free Research Field

代謝学

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。