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

Toshiaki Teratani, Kengo Tomita, Takahiro Suzuki, Hirotaka Furuhashi, Rie Irie, Shigeaki Hida, Yoshikiyo Okada, Chie Kurihara, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Hidetsugu Saito, Toshifumi Hibi, Soichiro Miura, Ryota Hokari, Takanori Kanai

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 fourweeks 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.

Original languageEnglish
JournalJournal of Hepatology
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Toll-Like Receptor 9
Acetaminophen
Endothelial Cells
Cholesterol
Liver
Inflammasomes
Wounds and Injuries
Acute Liver Failure
Endosomes
Pathology
Diet
Obesity
Membranes
Recycling
Lysosomes

Keywords

  • Acetaminophen
  • Endosome
  • Free cholesterol
  • Inflammasome
  • Liver injury
  • Liver sinusoidal endothelial cell
  • Lysosome
  • Metabolic syndrome
  • Rab7
  • Toll-like receptor 9

ASJC Scopus subject areas

  • Hepatology

Cite this

Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling. / Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Furuhashi, Hirotaka; Irie, Rie; Hida, Shigeaki; Okada, Yoshikiyo; Kurihara, Chie; Ebinuma, Hirotoshi; Nakamoto, Nobuhiro; Saito, Hidetsugu; Hibi, Toshifumi; Miura, Soichiro; Hokari, Ryota; Kanai, Takanori.

In: Journal of Hepatology, 2017.

Research output: Contribution to journalArticle

Teratani, Toshiaki ; Tomita, Kengo ; Suzuki, Takahiro ; Furuhashi, Hirotaka ; Irie, Rie ; Hida, Shigeaki ; Okada, Yoshikiyo ; Kurihara, Chie ; Ebinuma, Hirotoshi ; Nakamoto, Nobuhiro ; Saito, Hidetsugu ; Hibi, Toshifumi ; Miura, Soichiro ; Hokari, Ryota ; Kanai, Takanori. / Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling. In: Journal of Hepatology. 2017.
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title = "Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling",
abstract = "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 fourweeks 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.",
keywords = "Acetaminophen, Endosome, Free cholesterol, Inflammasome, Liver injury, Liver sinusoidal endothelial cell, Lysosome, Metabolic syndrome, Rab7, Toll-like receptor 9",
author = "Toshiaki Teratani and Kengo Tomita and Takahiro Suzuki and Hirotaka Furuhashi and Rie Irie and Shigeaki Hida and Yoshikiyo Okada and Chie Kurihara and Hirotoshi Ebinuma and Nobuhiro Nakamoto and Hidetsugu Saito and Toshifumi Hibi and Soichiro Miura and Ryota Hokari and Takanori Kanai",
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T1 - Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling

AU - Teratani, Toshiaki

AU - Tomita, Kengo

AU - Suzuki, Takahiro

AU - Furuhashi, Hirotaka

AU - Irie, Rie

AU - Hida, Shigeaki

AU - Okada, Yoshikiyo

AU - Kurihara, Chie

AU - Ebinuma, Hirotoshi

AU - Nakamoto, Nobuhiro

AU - Saito, Hidetsugu

AU - Hibi, Toshifumi

AU - Miura, Soichiro

AU - Hokari, Ryota

AU - Kanai, Takanori

PY - 2017

Y1 - 2017

N2 - 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 fourweeks 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.

AB - 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 fourweeks 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.

KW - Acetaminophen

KW - Endosome

KW - Free cholesterol

KW - Inflammasome

KW - Liver injury

KW - Liver sinusoidal endothelial cell

KW - Lysosome

KW - Metabolic syndrome

KW - Rab7

KW - Toll-like receptor 9

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U2 - 10.1016/j.jhep.2017.05.020

DO - 10.1016/j.jhep.2017.05.020

M3 - Article

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

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