Cited by 316Liver Disease Diagnosis and TreatmentLiver physiology and pathologyCholesterol and Lipid Metabolism

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Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice

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Tomita, Kengo, Teratani, Toshiaki, Suzuki, Takahiro, Shimizu, Motonori, Sato, Hirokazu, Narimatsu, Kazuyuki, Okada, Yoshikiyo, Kurihara, Chie, Irie, Rie, Yokoyama, Hirokazu, Shimamura, Katsuyoshi, Usui, Shingo, Ebinuma, Hirotoshi, Saito, Hidetsugu, Watanabe, Chikako, Komoto, Shunsuke, Kawaguchi, Atsushi, Nagao, Shigeaki, Sugiyama, Kazuo, Hokari, Ryota, Kanai, Takanori, Miura, Soichiro, Hibi, Toshifumi·2014·Hepatology

DOI 10.1002/hep.26604

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Abstract

Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by down-regulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated by way of a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 down-regulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. Conclusion : These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.

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BackgroundInfluential
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BackgroundInfluential
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Redox Signaling in NASH
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Authors: Tomita, K., Teratani, T., Suzuki, T., Shimizu, M., Sato, H., Narimatsu, K., Okada, Y., Kurihara, C., Irie, R., Yokoyama, H., Shimamura, K., Usui, S., Ebinuma, H., Saito, H., Watanabe, C., Komoto, S., Kawaguchi, A., Nagao, S., Sugiyama, K., Hokari, R., Kanai, T., Miura, S., & Hibi, T.
Affiliations: Keio University (JP)
National Defense Medical College (JP)
Kawasaki Municipal Hospital (JP)
Corresponding author: Tomita, Kengo
ORCID: Tomita, Kengo
Suzuki, Takahiro
Sato, Hirokazu
Narimatsu, Kazuyuki
Okada, Yoshikiyo
Kurihara, Chie
Irie, Rie
Ebinuma, Hirotoshi
Saito, Hidetsugu
Komoto, Shunsuke
Kawaguchi, Atsushi
Hokari, Ryota
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2014-01
Volume: 59
Issue: 1
Pages: 154-169
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1002/hep.26604
OpenAlex: W2155259249
Cited by: 315
References: 21
Citations by year: 2026: 18 · 2025: 27 · 2024: 21 · 2023: 22 · 2022: 27 · 2021: 35 · 2020: 32 · 2019: 25 · 2018: 33 · 2017: 22 · 2016: 22 · 2015: 15 · 2014: 15
FWCI: 12.83
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 608 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
Funders: Keio University
Saitama Medical University
Japan Society for the Promotion of Science (23590551, 24390190)
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords: free cholesterol, hepatic stellate cells, liver fibrosis, nonalcoholic steatohepatitis, hypercholesterolemia, TLR4, TGF-beta signaling, SREBP2, cholesterol homeostasis, PPARγ, methionine-choline-deficient diet, high-fat diet, Kupffer cells
MeSH terms: Animals, Cholesterol, Disease Models, Animal, Fatty Liver, Liver Cirrhosis, Macrophage Activation, Male, Membrane Proteins, Mice, Inbred C57BL, Receptors, LDL, RNA, Messenger, Signal Transduction, Down-Regulation, Up-Regulation, Transforming Growth Factor beta, MicroRNAs, PPAR gamma, Toll-Like Receptor 4, Mice, Sterol Regulatory Element Binding Protein 2, Hepatic Stellate Cells

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Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice

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