The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“High concentrations of cholesterol and free cholesterol accumulate in HSCs in methionine-choline deficient (MCD) MASH mice, which increases toll-like receptor 4 (TLR4) and sensitizes the cells to TGFβ–induced activation (148).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [148]
In the citing paper
“Mechanistically, cholesterol accumulation in cultured HSCs has been found to increase TLR4 abundance by suppressing its endosomal degradation, which sensitizes these cells to TGFβ-induced activation (148).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [148]
In the citing paper
“Studies on different strains of mice have shown that plasma cholesterol strongly correlates with the extent of fibrosis, and mice supplemented with high cholesterol develop increased fibrosis (148, 186).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [148]
In the citing paper
“In vivo studies have confirmed that TLR4 knockout MCD mice are protected against the profibrotic effect of cholesterol supplementation (187).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [187]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
TLR4 enhances TGF-β signaling and hepatic fibrosis
Seki, E., De Minicis, S., Österreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2007) · Nature Medicine · doi:10.1038/nm1663 · Cited by 1,942
Horton, J. D., Shah, N. A., Warrington, J. A., Anderson, N. N., Park, S. W., Brown, M. S., & Goldstein, J. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1534923100 · Cited by 1,270
A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
Brown, M. S., & Goldstein, J. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11041 · Cited by 1,134
CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis
Leclercq, I. A., Farrell, G. C., Field, J., Bell, D., Gonzalez, F. J., & Robertson, G. R. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8814 · Cited by 763
Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis
Marí, M., Caballero, F. G., Colell, A., Morales, A., Caballería, J., Fernandez, A., Enrich, C., Fernández-Checa, J. C., & García‐Ruiz, C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.07.006 · Cited by 624
Radhakrishnan, A., Goldstein, J. L., McDonald, J. G., & Brown, M. S. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.10.008 · Cited by 534
Adams, C. M., Reitz, J., Brabander, J. K. D., Feramisco, J. D., Li, L., Brown, M. S., & Goldstein, J. L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410302200 · Cited by 463
Tomita, K., Tamiya, G., Ando, S., Ohsumi, K., Chiyo, T., Mizutani, A., Kitamura, N., Toda, K., Kaneko, T., Horie, Y., et al. (2005) · Gut · doi:10.1136/gut.2005.071118 · Cited by 454
Self-citationBrown, A. J., Sun, L., Feramisco, J. D., Brown, M. S., & Goldstein, J. L. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00591-9 · Cited by 417
Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors
Chuang, T.-H., & Ulevitch, R. J. (2004) · Nature Immunology · doi:10.1038/ni1066 · Cited by 374
Cited by
Sorted by citations
Mechanisms of hepatic stellate cell activation
Tsuchida, T., & Friedman, S. L. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.38 · Cited by 2,909
Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002
“A key feature of the lipotoxic response is enhanced free cholesterol, which is directly fibrogenic toward stellate cells (Tomita et al., 2014).”
BackgroundHepatic stellate cells as key target in liver fibrosis
Higashi, T., Friedman, S. L., & Hoshida, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.007 · Cited by 1,485
Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives
Roehlen, N., Crouchet, E., & Baumert, T. F. (2020) · Cells · doi:10.3390/cells9040875 · Cited by 1,237
“also demonstrated that accumulation of free cholesterol in HSCs directly exacerbate liver fibrosis [49,50].”
BackgroundSREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology
Shimano, H., & Sato, R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.91 · Cited by 1,174
Metadata
- 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
- Venue
- Hepatology
- Published
- 2014-01
- Volume
- 59
- Issue
- 1
- Pages
- 154-169
- ISSN
- 0270-9139 (ISSN-L)
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
