The role of NCEH1 in obesity

• Project/Area Number: 20K08870
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Takahashi Manabu 自治医科大学, 医学部, 客員研究員 (70406122)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肥満 / マクロファージ / NCEH1 / コレステロールエステル加水分解酵素

Outline of Research at the Start

肥満や動脈硬化の病態形成にマクロファージが重要な役割を担っている。中性コレステロールエステル(CE)水解酵素1(NCEH1)は、マクロファージに豊富に発現し脂肪滴に蓄積したCEを加水分解する酵素である。NCEH1を欠損するマウスは、マクロファージのCE蓄積と動脈硬化の増悪を認める一方で、食餌性肥満(DIO)に抵抗性で、白色脂肪組織のマクロファージが減少していることを見出した。そこで、NCEH1欠損がDIOを抑制する機序の解明を目指す。

Outline of Final Research Achievements

Neutral cholesterol ester hydrolase 1 (NCEH1), which is abundantly expressed in macrophages, mediates the hydrolysis of CE accumulated as a lipid droplet. To elucidate the role of NCEH1 in obesity, NCEH1 knockout (NCEH1KO) mice were fed a high-fat diet for 24 weeks. Both NCEH1KO and control mice gained weight at similar rates over the entire observation period. NCEH1KO perigonadal fat pads were heavier than those from male control mice, while liver weights were lighter in NCEH1KO compared with control mice. NCEH1KO mice had lower levels of fasting plasma glucose and total cholesterol than control mice. Although further investigation should be required to determine the role of NCEH1 in obesity, NCEH1 may be involved in the pathogenesis of obesity.

Academic Significance and Societal Importance of the Research Achievements

肥満の病態形成において、マクロファージは重要な役割を担っている。そして、マクロファージの細胞内脂質代謝は炎症などの細胞機能に関わることが明らかになっている。本研究では、細胞内コレステロール代謝に関わるNCEH1の発現を調節することにより肥満病態における糖脂質代謝を制御する可能性が示唆され、意義のある成果と考えられる。

Research Products

• [Journal Article] Serum 25-hydroxycholesterol levels are increased in patients with coronavirus disease 2019 (2023)
  • Author(s): Takumi Asano, Tetsuji Wakabayashi, Yasuyuki Kondo, Kenta Okada, Daisuke Yamamuro, Yukiko Koga, Kiyonori Oka, Momoe Sakurai, Nagisa Sawayama, Manabu Takahashi, Hiroaki Okazaki, Ken Ebihara, Kensuke Minami, Yuji Morisawa, Shuji Hatakeyama, Masami Matsumura, Shun Ishibashi
  • Journal Title: Journal of Clinical Lipidology Volume: 17 Issue: 1 Pages: 78-86
  • DOI: 10.1016/j.jacl.2022.10.012
  • Peer Reviewed / Open Access
• [Journal Article] Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice (2022)
  • Author(s): Takahashi M, Yamamuro D, Wakabayashi T, Takei A, Takei S, Nagashima S, Okazaki H, Ebihara K, Yagyu H, Takayanagi Y, Onaka T, Goldberg IJ, Ishibashi S.
  • Journal Title: J Biol Chem Volume: 298 Issue: 9 Pages: 102322-102322
  • DOI: 10.1016/j.jbc.2022.102322
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AAA-ATPase valosin-containing protein binds the transcription factor SREBP1 and promotes its proteolytic activation by rhomboid protease RHBDL4. (2022)
  • Author(s): Shibuya K, Ebihara K, Ebihara C, Sawayama N, Isoda M, Yamamuro D, Takahashi M, Nagashima S, Ishibashi S
  • Journal Title: J Biol Chem Volume: 298 Issue: 6 Pages: 101936-101936
  • DOI: 10.1016/j.jbc.2022.101936
  • Peer Reviewed / Open Access