The role of p62 in NASH - analyses from the view of fatty acid metabolism and organ cross-talk

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07933
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Okada Kosuke 筑波大学, 医学医療系, 准教授 (80757526)
• Co-Investigator(Kenkyū-buntansha): 有泉 俊一 東京女子医科大学, 医学部, 准教授 (40277158) ; 正田 純一 筑波大学, 医学医療系, 客員教授 (90241827)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: NASH / p62 / autophagy / 脂肪酸代謝

Outline of Final Research Achievements

p62 knock-out mice in whole body (p62-KO) mice exhibit severe NASH fed by a high fat feeding compared with WT mice. To elucidate the mechanism of NASH from the view of organ cross-talks, hepatocyte, adipocyte, or macrophage including Kupffer cells specific conditional p62 knock-in (rescued) mice were analyzed in NASH development. The hepatocyte specific p62 rescued mice were suppressed the development of NASH with severe hepatic inflammation and fibrosis compared with other mice despite their similar obese.
p62 in hepatocytes changed the expression of factors of autophagy/lipophagy, and deletion of p62 in cultured hepatocytes led the apoptosis induced by oleic acid. These results indicates that p62 has the role in process of fatty acid metabolism through autophagy/lipophagy.
p62 in hepatocytes was considered to play a protective role against the development of NASH. p62 of hepatocytes could be a new and promising target for treatment of NASH.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪性肝炎（NASH）は，頻度の高い生活習慣関連肝疾患であるが，致死的な肝硬変，肝癌へ進行し得る．しかし，その発症機序は完全には解明されておらず，NASH進行および肝癌発生を阻止するための薬物治療も確立していない．本研究は，肝細胞特異的なp62発現がNASHの進展を抑止することを見出した．これらの結果から肝細胞のp62がNASHに防御的な役割を果たすと考えられ，特に肝細胞のp62の発現が，肝脂肪化のみならず肝炎症線維化をもコントロールする可能性を示した．本研究はp62が新しいNASHの治療標的と成り得る可能性を示した点で，将来的なNASH治療開発のための意義が大きい．