Role of the crosstalk between liver and brain in the pathophysiology of liver fibrosis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16KT0110
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Nagoya University
• Principal Investigator: Suganami Takayoshi 名古屋大学, 環境医学研究所, 教授 (50343752)
• Co-Investigator(Kenkyū-buntansha): 山中 宏二 名古屋大学, 環境医学研究所, 教授 (80446533)
• Research Collaborator: Itoh Michiko
• Project Period (FY): 2016-07-19 – 2019-03-31
• Keywords: NASH / マクロファージ / 慢性炎症 / 線維化 / MC4R

Outline of Final Research Achievements

Various chronic inflammatory diseases including lifestyle-related diseases eventually result in tissue fibrosis, which has major unmet medical needs. In this study, to understand the molecular mechanism underlying NASH, we employed genetically obese melanocortin-4 receptor-deficient mice, which sequentially developed simple steatosis, NASH, and hepatocellular carcinoma (HCC) when they were fed a Western diet. We found that tissue-resident macrophages in the liver or Kupffer cells aggregate around dead or dying hepatocytes to form a unique histological structure termed crown-like structure, thereby accelerating liver fibrosis. Interestingly, these Kupffer cells showed a phenotypic change to obtain the profibrotic property. We also found that MC4R in the hypothalamus is capable of regulating chemotactic activity of macrophages in the liver, particularly in the resolution phase.

Free Research Field

内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

肝線維化のメカニズムとして、肝細胞死に引き続くマクロファージや線維芽細胞の活性化が指摘されているが、本研究において、慢性炎症や線維化の起点となる微小環境が初めて明らかになった。また、同様の微小環境が脂肪組織や腎臓などにおいても観察され、その共通性や臓器特異性を明らかにすることで、慢性炎症性疾患に対する理解が深まると期待される。最近、MC4R作動薬など中枢神経系を標的とする抗肥満薬の開発が進んでいる。中枢性の炎症制御機構の解明は、新たな抗肥満薬の臨床応用に貢献すると考えられる。