Understanding of molecular mechanism for inhibition of NASH development by p62-Approach in terms of fatty acid energy metabolism

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19887
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Health science and related fields
• Research Institution: University of Tsukuba
• Principal Investigator: Shoda Junichi 筑波大学, 医学医療系, 教授 (90241827)
• Co-Investigator(Kenkyū-buntansha): 蕨 栄治 筑波大学, 医学医療系, 講師 (70396612) ; 岡田 浩介 筑波大学, 附属病院, 病院講師 (80757526)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 非アルコール性脂肪性肝疾患 / NASH / p62 / 脂肪酸代謝

Outline of Final Research Achievements

We generated p62 knockout (p62-KO) mice and demonstrated that these mice developed to simple steatosis in the livers by the obesity caused by hyperphagia. Moreover, we found that p62-KO mice developed severe steatohepatitis induced by a 60% high fat diet (HFD). We supposed the mechanism for the development of steatohepatitis in p62-KO mice fed HFD that p62 influenced free fatty acid (FFA) metabolism and resulted in the unbalance between FFA and fatty acyl-CoA in the hepatocytes. TG levels in p62-KO hepatocytes was increased compared with WT hepatocytes, and these results suggest that deletion of p62 could be associated with the functional change of “lipophagy”, the important and new system of the metabolism for TG to FFA. To elucidate the regulatory role of p62 in NASH more clearly, we plan to compare the phenotypes between p62-KO and p62 gene rescued mice in hepatocytes, and p62 knockout hepatocytes and WT hepatocytes.

Free Research Field

健康応用科学

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪性肝炎（NASH）は，単純性脂肪肝から発生し，肝硬変，肝癌へ進行する致死的疾患にも関わらず，その発症機序は未解明で，確立された薬物治療も存在しない．本研究は，p62-KOマウスに高脂肪食を摂餌させるという簡便な方法でヒトNASHに類似する新規モデルを作製したことにより，NASHの発症メカニズム解明に寄与すると考えられる．また，p62がFFA代謝を介してNASHに対して防御的な役割を果たすことを示唆し，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意義が大きい．