TY - JOUR
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
N1 - Publisher Copyright:
© 2017 European Association for the Study of the Liver
PY - 2017/10
Y1 - 2017/10
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 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.
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 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.
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
C2 - 28554874
AN - SCOPUS:85021856061
SN - 0168-8278
VL - 67
SP - 780
EP - 790
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -
