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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 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]
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“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]
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“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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Yan, M., Cui, Y., & Xiang, Q. (2025) · Theranostics · doi:10.7150/thno.106597 · Cited by 88
Vega‐Badillo, J., Gutiérrez‐Vidal, R., Hernández‐Pérez, H. A., Villamil‐Ramírez, H., León‐Mimila, P., Sánchez‐Muñoz, F., Morán‐Ramos, S., Larrieta‐Carrasco, E., Fernández‐Silva, I., Méndez‐Sánchez, N., et al. (2016) · Liver International · doi:10.1111/liv.13109 · Cited by 75
“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
Herrera, B. M., Addante, A., & Sánchez, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms19010039 · Cited by 79
Cai, C. X., Buddha, H., Castelino‐Prabhu, S., Zhang, Z., Britton, R. S., Bacon, B. R., & Neuschwander‐Tetri, B. A. (2017) · Digestive Diseases and Sciences · doi:10.1007/s10620-017-4470-9 · Cited by 76
“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 74
Nishiga, M., Horie, T., Kuwabara, Y., Nagao, K., Baba, O., Nakao, T., Nishino, T., Hakuno, D., Nakashima, Y., Nishi, H., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.309528 · Cited by 71
“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
Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity
Gupta, G., Khadem, F., & Uzonna, J. E. (2018) · Cytokine · doi:10.1016/j.cyto.2018.09.004 · Cited by 72
FOXO transcription factors protect against the diet-induced fatty liver disease
Pan, X., Zhang, Y., Kim, H.-G., Liangpunsakul, S., & Dong, X. C. (2017) · Scientific Reports · doi:10.1038/srep44597 · Cited by 67
Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease
Bécares, N., Gage, M., Voisin, M., Shrestha, E., Martin‐Gutierrez, L., Liang, N., Louie, R., Pourcet, B., Pello, Ó. M., Luong, T. V., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.094 · Cited by 69
Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis
Suga, T., Yamaguchi, H., Ogura, J., Shoji, S., Maekawa, M., & Mano, N. (2019) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2019.114664 · Cited by 70
Peng, H. Y., Yang, M., Feng, K., Lv, Q., & Zhang, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01887-0 · Cited by 69
“54 HMGCR, a key enzyme in cholesterol biosynthesis, promotes HCC growth.”
BackgroundSoleimani, D., Ranjbar, G., Rezvani, R., Goshayeshi, L., Razmpour, F., & Nematy, M. (2019) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s198744 · Cited by 67
“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 66
“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
Zhou, F., & Sun, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.762828 · Cited by 69
“The activated HSCs are then differentiated into myofibroblasts and accelerate fibrosis (Figure 2).”
BackgroundInfluentialLipotoxicity as the Leading Cause of Non-Alcoholic Steatohepatitis
Branković, M., Jovanović, I., Dukić, M., Radonjić, T., Oprić, S., Klašnja, S., & Zdravkovic, M. D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095146 · Cited by 72
“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].”
BackgroundLi, S., He, Y., Lin, S., Hao, L., Ye, Y., Lv, L. L., Sun, Z., Fan, H., Shi, Z., Li, J., et al. (2015) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201500425 · Cited by 64
“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
Grattagliano, I., Montezinho, L. P., Oliveira, P. J., Frühbeck, G., Gómez‐Ambrosi, J., Montecucco, F., Carbone, F., Wieckowski, M. R., Wang, D. Q. ‐., & Portincasa, P. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.11.020 · Cited by 66
Long-chain fatty acid activates hepatocytes through CD36 mediated oxidative stress
Liu, J., Yang, P., Zuo, G., He, S., Tan, W., Zhang, X., Su, C., Zhao, L., Li, W., Chen, Y., et al. (2018) · Lipids in Health and Disease · doi:10.1186/s12944-018-0790-9 · Cited by 62
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Therapeutic application of GPR119 ligands in metabolic disorders
Yang, J. W., Kim, H. S., Choi, Y., Kim, Y., & Kang, K. W. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13062 · Cited by 63
Teratani, T., Tomita, K., Furuhashi, H., Sugihara, N., Higashiyama, M., Nishikawa, M., Irie, R., Takajo, T., Wada, A., Horiuchi, K., et al. (2019) · Hepatology Communications · doi:10.1002/hep4.1383 · Cited by 56
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“In line with this notion, emerging experimental evidence implicates free cholesterol as a potential trigger of inflammation [5] as well as a possible driving factor in the development of fibrosis [6, 7].”
BackgroundGrgurević, I., Božin, T., Mikuš, M., Kukla, M., & O’Beirne, J. P. (2021) · Cancers · doi:10.3390/cancers13225844 · Cited by 58
“According to the given evidence, there is a strong association between TM6SF2 and multiple aspects of metabolic-syndrome–related end-organ damage [53].”
BackgroundAortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis
Teratani, T., Tomita, K., Suzuki, T., Furuhashi, H., Irie, R., Nishikawa, M., Yamamoto, J., Hibi∥, T., Miura, S., Minamino, T., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci92863 · Cited by 57
“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].”
BackgroundJiang, S., Yang, X., Yang, Z., Li, J., Xu, M., Qu, Y.-X., Tang, J., Li, Y., Wang, L., Shao, Y., et al. (2022) · Hepatology · doi:10.1002/hep.32381 · Cited by 58
“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).”
BackgroundAnimal Models of Fibrosis in Nonalcoholic Steatohepatitis: Do They Reflect Human Disease?
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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].”
BackgroundMéndez‐Sánchez, N., Reyes, E. C., la Tijera, F. H., Salas-García, A. K., Cabrera-Palma, S., Cabrera-Álvarez, G., Cortéz-Hernández, C. A., Pérez-Arredondo, L. A., Purón-González, E., Coronado-Alejandro, E., et al. (2020) · F1000Research · doi:10.12688/f1000research.21918.1 · Cited by 51
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
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