Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling

被引：30

作者：

Teratani, Toshiaki ^{[1
]}

Tomita, Kengo ^{[2
]}

Suzuki, Takahiro ^{[1
]}

Furuhashi, Hirotaka ^{[2
]}

Irie, Rie ^{[3
]}

Hida, Shigeaki ^{[4
,6
]}

Okada, Yoshikiyo ^{[2
]}

Kurihara, Chie ^{[2
]}

Ebinuma, Hirotoshi ^{[1
]}

Nakamoto, Nobuhiro ^{[1
]}

Saito, Hidetsugu ^{[5
]}

Hibi, Toshifumi ^{[1
]}

Miura, Soichiro ^{[2
]}

Hokari, Ryota ^{[2
]}

Kanai, Takanori ^{[1
]}

机构：

[1] Keio Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol,Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[2] Natl Def Med Coll, Dept Internal Med, Div Gastroenterol & Hepatol, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan

[3] Natl Ctr Child Hlth & Dev, Dept Pathol, Setagaya Ku, 2-10-1 Okura, Tokyo 1578535, Japan

[4] Shinshu Univ, Grad Sch Med, Inst Biomed Sci, Dept Mol Oncol, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan

[5] Keio Univ, Fac Pharm, Grad Sch Pharmaceut Sci, Minato Ku, 1-5-30 Shibakoen, Tokyo 1058512, Japan

[6] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Mol & Cellular Hlth Sci, Mizuho Ku, 3-1 Tanabe Dori, Nagoya, Aichi 4678603, Japan

来源：

JOURNAL OF HEPATOLOGY | 2017年 / 67卷 / 04期

关键词：

Free cholesterol; Liver sinusoidal endothelial cell; Acetaminophen; Liver injury; Rab7; Toll-like receptor 9; Endosome; Lysosome; Inflammasome; Metabolic syndrome; STERILE INFLAMMATION; EATING PATTERNS; HEPATITIS-C; RAB GTPASES; MICE; TRAFFICKING; RECOGNITION; RECEPTORS; FIBROSIS; MODEL;

D O I：

10.1016/j.jhep.2017.05.020

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA. Methods: C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9(-/-)) mice and their Tlr9(+/+) littermates were fed an HC diet for four weeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses. Results: 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. Conclusions: HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen-induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism. Thus, free cholesterol accumulation, as an underlying metabolic factor, exacerbated the pathology of acetaminophen-induced liver injury through activation of the TLR9/inflammasome pathway. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

引用

页码：780 / 790

页数：11

共 31 条

[1] DNase II-dependent DNA digestion is required for DNA sensing by TLR9 [J].