Role of the immunoproteasome in nonalcoholic steatohepatitis

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07365
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kyushu University of Health and Welfare
• Principal Investigator: Kimura Hiroaki 九州保健福祉大学, 薬学部, 教授 (70593622)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 免疫プロテアソーム / LMP2 / LMP7 / 非アルコール性脂肪性肝炎 / NASH / 炎症

Outline of Final Research Achievements

The goal of the study is to unveil the role of the immunoproteasome enzyme subunits, LMP2 and LMP7 in the pathogenesis of non-alcoholic steatohepatitis (NASH). We used LMP2 and LMP7 knockout mice, because the enzymatic activity between LMP2 and LMP7 is different. When we induced NASH in the mice, we found differences of the disease grade between those mice. LMP7 had promotive role in the early stage of the NASH pathogenesis. On the other hand, LMP2 had protective role in the early stage of the NASH pathogenesis. Both mice developed similar level of staeatosis and mononuclear cell (MNCs) infiltrations. However, the population of MNCs seemed different. The detail of the population should be identified. We assessed if the immunoproteasome influences lipid accumulation in hepatocytes in vitro using inhibitors and gene-knokckout technology. How ever we found the immunoprotesome didn't influence the accumulation.

Free Research Field

内分泌学・炎症・免疫学

Academic Significance and Societal Importance of the Research Achievements

我々の結果は、学術的にはおもしろい発見であるといえる。以前に橋本病モデルでも得られたのだが、LMP2とLMP7の役割が正反対であった。これらの分子は、プロテアソームに組み込まれる前に前駆体として存在し、自身の酵素活性で自己切断する。つまり、プロテアソームに組み込まれる前にも酵素活性を持っていることから何かしらユニークな制御があると考えられる。また、社会的にも、貢献できる可能性がある。LMP7がNASH発症に誘導的に働くことから、予防として阻害剤の利用が可能かどうか調べることによって、新規予防/治療法の可能性を見出したと言える。