Establishment of novel therapies for steatohepatitis and liver cancer, by targeting the free cholesterol-mediated signaling pathway.

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09031
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: National Defense Medical College
• Principal Investigator: Tomita Kengo 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 病院 内科, 准教授 (50317129)
• Co-Investigator(Renkei-kenkyūsha): SHIMIZU Takahiko 千葉大学, 医学部, 客員准教授 (40301791)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 非アルコール性脂肪肝炎 / 遊離コレステロール / TLR9 / アセトアミノフェン肝障害 / 類洞内皮細胞

Outline of Final Research Achievements

The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs.

Free Research Field

脂肪肝炎