Clarification of pathogenesis of NASH(non-alcoholic steatohepatitis) using PDLIM2-deficient mice

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K08536
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: TANAKA TAKASHI 国立研究開発法人理化学研究所, 統合生命医科学研究センター, チームリーダー (00415225)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 非アルコール性脂肪肝炎（NASH） / PDLIM2 / ユビキチンリガーゼ / 腸内細菌 / 脂質代謝

Outline of Final Research Achievements

NASH is a chronic hepatic inflammation associated with immune cell infiltration and fibrosis. We recently found that mice deficient in PDLIM2, a nuclear ubiquitin E3 ligase containing PDZ and LIM domains, spontaneously develop NASH-like pathology. Notably, PDLIM2-deficient mice develop NASH in the animal facility of Harvard University, but not in RIKEN facility. Since systemic inflammation can be modified by gut microbiota, we colonized gut microbiota of mice form Taconic Farms into germ-free PDLIM2-deficient mice, and found that PDLIM2-deficient mice with Taconic microbiota environment could develop NASH when we fed a normal chow or higher fat diet (9-15% fat). Microarray analysis of Kupffer cells in PDLIM2-deficient liver showed the upregulation inflammation and metabolism-related genes, which contribute to the NASH phenotype. These data suggest that Taconic microbiota or microbiota-derived metabolites are essential for the development of NASH in combination with PDLIM2-deficiency.

Free Research Field

免疫学