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.
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High cholesterol and free cholesterol accumulation in HSCs in MCD MASH mice increases TLR4 and sensitizes the cells to TGFβ-induced activation.
“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]
Cholesterol accumulation in cultured HSCs increases TLR4 abundance by suppressing endosomal degradation, sensitizing the cells to TGFβ-induced activation.
“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]
Studies in different mouse strains show that plasma cholesterol strongly correlates with fibrosis extent, and high-cholesterol supplementation increases fibrosis.
“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]
TLR4 knockout MCD mice are protected against the profibrotic effect of cholesterol supplementation.
“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]
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“It has been suggested that FC activates HSCs by rendering them susceptible to transforming growth factor (TGF) β signaling [107].”
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“Tontonoz and colleagues reported several years ago [49] and, more recently, Tomita and colleagues together provide a molecular explanation for cholesterol as a profibrogenic substance [28].”
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“Free cholesterol accumulation caused-lipotoxicity sensitizes HSCs to TGFβ-induced activation through TLR4 signaling in NASH mouse model [155].”
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“Importantly, increased cholesterol accumulation in HSCs accelerates liver fibrosis, and thus enhanced efflux through ABCA1 and ABCG1 induction while reducing ACAT2 may be additional mechanisms by which Aramchol reduces HSC fibrogenesis.(23) We performed GSEA to identify other cellular pathways responsive to Aramchol (…”
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“Recent research suggests that free cholesterol accumulation in hepatic stellate cells aggravates liver fibrosis in NASH in the murine model, possibly by increasing miR-33a levels which in turn would suppress ABCA1 levels (23).”
BackgroundBMP Signalling at the Crossroad of Liver Fibrosis and Regeneration
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“The selection for a 24-week feeding time was based upon the successful production of NASH-fibrosis close to human NASH in both mice [20] and rats [42, 43].”
BackgroundTGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis: Updated
Dewidar, B., Soukupová, J., Fabregat, I., & Dooley, S. (2015) · Current Pathobiology Reports · doi:10.1007/s40139-015-0089-8 · Cited by 71 · see citing works
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“It was also reported that miR-33 is involved in inflammatory processes in atherosclerotic lesions(29) and fibrotic responses in the liver.(30) However, the functions of miR-33 in cardiac hypertrophy and heart failure, which are also chronic inflammatory and fibrotic processes as mentioned above, remain to be elucidate…”
BackgroundResultInfluentialThe Genetic Architecture of Diet‐Induced Hepatic Fibrosis in Mice
Hui, S. T., Kurt, Z., Tuominen, I., Norheim, F., C.Davis, R., Pan, C., Dirks, D. L., Magyar, C. E., French, S. W., Chella Krishnan, K., et al. (2018) · Hepatology · doi:10.1002/hep.30113 · Cited by 66 · see citing works
Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity
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FOXO transcription factors protect against the diet-induced fatty liver disease
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Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease
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Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis
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“54 HMGCR, a key enzyme in cholesterol biosynthesis, promotes HCC growth.”
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“It is suggested that the Western dietary pattern, with its pro-inflammatory properties, could promote hepatic inflammation and fibrogenesis through the Kupffer cells and hepatic stellate cell activation.(8,29) The Iranian dietary pattern in our study included a high intake of high-fat dairies, refined grains, legumes,…”
BackgroundGenetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis
Price, N. L., Miguel, V., Ding, W. J., Singh, A. K., Malik, S., Rotllán, N., Moshnikova, A., Toczek, J., Zeiss, C. J., Sadeghi, M. M., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.131102 · Cited by 67 · see citing works
“Earlier work has suggested that miR-33 may play a role in the regulation of hepatic fibrosis, as it was reported that inhibition of miR-33 reduces the mRNA expression of some fibrosis-associated factors in a nonalcoholic steatohepatitis model (57).”
Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma
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“The activated HSCs are then differentiated into myofibroblasts and accelerate fibrosis (Figure 2).”
BackgroundInfluentialLipotoxicity as the Leading Cause of Non-Alcoholic Steatohepatitis
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“In addition, free cholesterol means the increasing vulnerability of hepatic stellate cells to transformative growth factor (TGF) β signaling, and in that way, it promotes fibrosis in NASH [53].”
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“Liver plays the central role in maintaining cholesterol homeostasis through a feedback regulation mediated by sterol regulatory element-binding protein 2 (SREBP-2) [18].”
BackgroundTargeting mitochondria to oppose the progression of nonalcoholic fatty liver disease
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BackgroundAortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis
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“lated from mice and cultured as previously described (15).”
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“Activated HSCs could sensitize the cell injury to further enhance lipid accumulation when there is increased intake of cholesterol, which may lead a vicious cycle in NASH, namely, accumulated lipids activating HSCs and the latter resulting in more accumulation of lipids in these cells [31].”
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“Such distributions of cholesterol crystals and KCs were previously reported to be key features for distinguishing NASH from SS.[34] Importantly, 25- HL and OCA profoundly reduced the numbers of crown- like structure and cholesterol crystals in a dose- dependent fashion (Figure 6J,K).”
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Liver X receptors and liver physiology
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“Dysregulation of DNL and cholesterol synthesis in liver metabolism is a feature of NASH [11,12] and fibrogenesis [13].”
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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
- 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 · 2013: 1
- 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 › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › 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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