Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling
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説明
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.C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9The 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.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.
収録刊行物
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- Journal of Hepatology
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Journal of Hepatology 67 (4), 780-790, 2017-10
Elsevier BV
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キーワード
- Male
- Mice, Knockout
- Inflammasomes
- Endothelial Cells
- rab7 GTP-Binding Proteins
- Diet, High-Fat
- Mice, Inbred C57BL
- Mice
- Protein Transport
- Cholesterol
- Liver
- Oligodeoxyribonucleotides
- rab GTP-Binding Proteins
- Toll-Like Receptor 9
- Animals
- Chemical and Drug Induced Liver Injury
- Lysosomes
- Acetaminophen
- Signal Transduction
詳細情報 詳細情報について
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- CRID
- 1360567182234374912
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- ISSN
- 01688278
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- PubMed
- 28554874
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- 資料種別
- journal article
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- データソース種別
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- Crossref
- KAKEN
- OpenAIRE
