The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis
Open accessAbstract
Background and aims The farnesoid X receptor (FXR) is an endogenous sensor for bile acids and inhibits bile acid synthesis by inducing small heterodimer partner (SHP) gene expression. The aim of this study was to investigate whether FXR is expressed by and modulates function of hepatic stellate cells (HSCs).Methods The antifibrotic activity of FXR ligand was tested in 2 rodent models: the porcine serum and bile duct ligation (BDL).Results Twelve-week administration of 1-10 mg/kg 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic FXR ligand, to porcine serum-treated rats prevented liver fibrosis development and reduced liver expression of alpha1(I) collagen, TGF-beta1 and alpha-SMA mRNA by approximately 90%. Therapeutic administration of 6-ECDCA, 3 mg/kg, to BDL rats reduced liver fibrosis and alpha1(I) collagen, transforming growth factor (TGF)-beta1, alpha-SMA, and tissue metalloproteinase inhibitor (TIMP)-1 and 2 messenger RNA (mRNA) by 70%-80%. No protection was observed in BDL rats treated with CDCA, 3 mg/kg, and ursodeoxycholic acid, 15 mg/kg. FXR expression was detected in HSCs. Exposure of HSCs to FXR ligands caused a 3-fold increase of SHP, reduced alpha1(I)collagen and TGF-beta1 by approximately 60%-70% and abrogates alpha1(I) collagen mRNA up-regulation induced by thrombin and TGF-beta1. By retrovirus infection and small interference RNA, we generated SHP overexpressing and SHP-deficient HSC-T6. Using these cell lines, we demonstrated that SHP binds JunD and inhibits DNA binding of adaptor protein (AP)-1 induced by thrombin.Conclusions By demonstrating that an FXR-SHP regulatory cascade promotes resolution of liver fibrosis, this study establish that FXR ligands might represent a novel therapeutic option to treat liver fibrosis.
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Upregulation of SHP might lead to the major anti-fibrotic activity of FXR.
“Fiorucci et al. investigated the role of SHP in HSC inhibition, concluding that upregulation of SHP might lead to the major anti-fibrotic activity of FXR.[61,62]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [61]
The direct impact of FXR activation on liver fibrosis is still controversially discussed because there is partially conflicting data on FXR mRNA and protein expression in hepatic stellate cells and myofibroblasts.
“Nevertheless, the direct impact of FXR activation on liver fibrosis is still controversially discussed as there is partially conflicting data on FXR mRNA and protein expression in HSC and myofibrobasts.[57,61]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [61]
Hepatic stellate cells exposed to an FXR ligand show reduced expression of col1α1 and TGF-β and upregulation of the nuclear receptor NR0B2/SHP.
“In vitro experiments demonstrated that HSCs exposed to an FXR ligand show a reduced expression of alpha-1 type 1 collagen (col1α1) and TGF-β and an upregulation of the nuclear receptor NR0B2 -the small heterodimer partner (SHP).[61]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [61]
Activation of the FXR-SHP cascade by FXR agonism seemed to protect against liver fibrosis in another bile duct ligation model.
“Furthermore, the activation of the FXR-SHP cascade by FXR agonism seemed to protect against liver fibrosis in another bile duct ligation model.[61]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [61]
Fiorucci et al. found FXR gene and protein expression in rat hepatic stellate cells and in the passaged cell line HSC-T6, while Fickert et al. reported only marginal expression levels of FXR in human hepatic stellate cells and undetectable FXR protein expression in mouse hepatic stellate cells.
“While Fiorucci et al. found FXR gene and protein expression in rat HSCs and in a passaged cell line HSC-T6 [61], Fickert et al. reported only marginally expression levels of FXR in human HSCs and undetectable FXR protein expression in mouse HSCs.[57]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [61]
Various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models.
“Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [37]
Some studies demonstrated that FXR was positively expressed and functionally active in HSCs.
“Some studies demonstrated that FXR was positively expressed and functionally active in HSCs37.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [37]
Activation of FXR in HSCs results in up-regulation of SHP, which binds JunD and inhibits DNA binding of adaptor protein-1.
“Activation of FXR in HSCs results in up-regulation of SHP, which binds JunD and inhibits DNA binding of adaptor protein-137.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [37]
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Cites
Real time quantitative PCR.Preprint
Heid, C., Stevens, J., Livak, K. J., & Williams, P. (1996) · Genome Research · doi:10.1101/gr.6.10.986 · Cited by 6,180 · see citing works
RNA interference is mediated by 21- and 22-nucleotide RNAsPreprint
Elbashir, S. M., Lendeckel, W., & Tuschl, T. (2001) · Genes & Development · doi:10.1101/gad.862301 · Cited by 3,310 · see citing works
Identification of a nuclear receptor for bile acids
Makishima, M., Okamoto, A. Y., Repa, J. J., Tu, H., Learned, R. M., Luk, A., Hull, M. V., Lustig, K. D., Mangelsdorf, D. J., & Shan, B. (1999) · Science · doi:10.1126/science.284.5418.1362 · Cited by 2,714 · see citing works
Bile Acids: Natural Ligands for an Orphan Nuclear Receptor
Parks, D. J., Blanchard, S. G., Bledsoe, R. K., Chandra, G., Consler, T. G., Kliewer, S. A., Stimmel, J. B., Willson, T. M., Zavacki, A. M., Moore, D. D., et al. (1999) · Science · doi:10.1126/science.284.5418.1365 · Cited by 2,274 · see citing works
Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury
Friedman, S. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.4.2247 · Cited by 2,090 · see citing works
A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis
Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00051-4 · Cited by 1,940 · see citing works
Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis
Sinal, C. J., Tohkin, M., Miyata, M., Ward, J. M., Lambert, G., & Gonzalez, F. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00062-3 · Cited by 1,819 · see citing works
Liver fibrosis – from bench to bedside
Friedman, S. L. (2003) · Journal of Hepatology · doi:10.1016/s0168-8278(02)00429-4 · Cited by 1,780 · see citing works
Endogenous Bile Acids Are Ligands for the Nuclear Receptor FXR/BAR
Wang, H., Chen, J., Hollister, K., Sowers, L. C., & Forman, B. M. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80348-2 · Cited by 1,636 · see citing works
Molecular Basis for Feedback Regulation of Bile Acid Synthesis by Nuclear Receptors
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., & Mangelsdorf, D. J. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00050-2 · Cited by 1,487 · see citing works
Histone modifications in transcriptional regulation
Berger, S. L. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00279-4 · Cited by 1,222 · see citing works
Identification of a nuclear receptor that is activated by farnesol metabolites
Forman, B. M., Goode, E., Chen, J., Oro, A. E., Bradley, D. J., Perlmann, T., Noonan, D. J., Burka, L. T., McMorris, T., Lamph, W. W., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90530-8 · Cited by 1,210 · see citing works
Iredale, J. P., Benyon, R. C., Pickering, J., McCullen, M., Northrop, M., Pawley, S., Hovell, C., & Arthur, M. J. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1018 · Cited by 1,075 · see citing works
Kast, H. R., Goodwin, B., Tarr, P. T., Jones, S. A., Anisfeld, A. M., Stoltz, C. M., Tontonoz, P., Kliewer, S., Willson, T. M., & Edwards, P. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109326200 · Cited by 916 · see citing works
Ananthanarayanan, M., Balasubramanian, N., Makishima, M., Mangelsdorf, D. J., & Suchy, F. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011610200 · Cited by 804 · see citing works
Paumgartner, G., & Beuers, U. (2002) · Hepatology · doi:10.1053/jhep.2002.36088 · Cited by 748 · see citing works
Pellicciari, R., Fiorucci, S., Camaioni, E., Clerici, C., Costantino, G., Maloney, P. R., Morelli, A., Parks, D. J., & Willson, T. M. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm025529g · Cited by 743 · see citing works
Self-citationProlonged bile duct obstruction: a new experimental model for cirrhosis in the rat.
Kountouras, J., Billing, B. H., & Scheuer, P. J. (1984) · PubMed · Cited by 679 · see citing works
León, A. L.-D., & Rojkind, M. (1985) · Journal of Histochemistry & Cytochemistry · doi:10.1177/33.8.2410480 · Cited by 607 · see citing works
Targeting JNK for therapeutic benefit: from junk to gold?
Manning, A. M., & Davis, R. J. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1132 · Cited by 585 · see citing works
Identification of a Chemical Tool for the Orphan Nuclear Receptor FXR
Maloney, P., Parks, D. J., Haffner, C. D., Fivush, A. M., Chandra, G., Plunket, K. D., Creech, K. L., Moore, L. B., Wilson, J. G., Lewis, M. C., et al. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm0002127 · Cited by 536 · see citing works
Apoptosis: The nexus of liver injury and fibrosis
Canbay, A. E., Friedman, S. L., & Gores, G. J. (2004) · Hepatology · doi:10.1002/hep.20051 · Cited by 529 · see citing works
Seol, W., Choi, H.-S., & Moore, D. D. (1996) · Science · doi:10.1126/science.272.5266.1336 · Cited by 528 · see citing works
Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors
Chiang, J. Y. L. (2002) · Endocrine Reviews · doi:10.1210/er.2000-0035 · Cited by 481 · see citing works
Pinzani, M., Gesualdo, L., Sabbah, G. M., & Abboud, H. E. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114363 · Cited by 477 · see citing works
Redundant Pathways for Negative Feedback Regulation of Bile Acid Production
Wang, L., Lee, Y., Bundman, D. S., Han, Y., Thevananther, S., Kim, C.-S., Chua, S. S., Wei, P. Y., Heyman, R. A., Karin, M., et al. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00187-9 · Cited by 475 · see citing works
Galli, A., Crabb, D. W., Ceni, E., Salzano, R., Mello, T., Svegliati–Baroni, G., Ridolfi, F., Trozzi, L., Surrenti, C., & Casini, A. (2002) · Gastroenterology · doi:10.1053/gast.2002.33666 · Cited by 440 · see citing works
Marra, F., Efsen, E., Romanelli, R. G., Caligiuri, A., Pastacaldi, S., Batignani, G., Bonacchi, A., Caporale, R., Laffi, G., Pinzani, M., et al. (2000) · Gastroenterology · doi:10.1053/gast.2000.9365 · Cited by 409 · see citing works
Liu, Y., Binz, J. G., Numerick, M. J., Dennis, S., Luo, G., Desai, B., MacKenzie, K. I., Mansfield, T. A., Kliewer, S. A., Goodwin, B. J., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18945 · Cited by 398 · see citing works
Gupta, S., Stravitz, R. T., Dent, P., & Hylemon, P. B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010878200 · Cited by 322 · see citing works
Hazra, S., Xiong, S., Wang, J., Rippe, R. A., Krishna, V., Chatterjee, K., & Tsukamoto, H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310284200 · Cited by 320 · see citing works
Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR
Mi, L.-Z., Devarakonda, S., Harp, J. M., Han, Q., Pellicciari, R., Willson, T. M., Khorasanizadeh, S., & Rastinejad, F. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00112-6 · Cited by 315 · see citing works
Self-citationVogel, S., Piantedosi, R., Frank, J., Lalazar, A., Rockey, D. C., Friedman, S. L., & Blaner, W. S. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32030-7 · Cited by 283 · see citing works
Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo.
Rockey, D. C., Housset, C., & Friedman, S. L. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116769 · Cited by 268 · see citing works
Yoshiji, H., Kuriyama, S., Miyamoto, Y., Thorgeirsson, U. P., Gomez, D. E., Kawata, M., Yoshii, J., Ikenaka, Y., Noguchi, R., Tsujinoue, H., et al. (2000) · Hepatology · doi:10.1053/jhep.2000.20521 · Cited by 254 · see citing works
Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)
Zhang, M., & Chiang, J. Y. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105117200 · Cited by 244 · see citing works
Iredale, J. P., Murphy, G., Hembry, R. M., Friedman, S. L., & Arthur, M. J. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115850 · Cited by 202 · see citing works
Rockey, D. C., & Chung, J. J. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118925 · Cited by 199 · see citing works
Transcriptional regulation of hepatic stellate cell activation: Figure 1
Mann, D. A., & Smart, D. E. (2002) · Gut · doi:10.1136/gut.50.6.891 · Cited by 190 · see citing works
Fiorucci, S., Antonelli, E., Distrutti, E., Severino, B., Fiorentina, R., Baldoni, M., Caliendo, G., Santagada, V., Morelli, A., & Cirino, G. (2004) · Hepatology · doi:10.1002/hep.20054 · Cited by 176 · see citing works
Self-citationHellemans, K., Michalik, L., Dittie, A., Knorr, A., Rombouts, K., de Jong, J., Heirman, C., Quartier, E., Schuit, F., Wahli, W., et al. (2003) · Gastroenterology · doi:10.1053/gast.2003.50015 · Cited by 137 · see citing works
Role of Mesenchymal Cell Populations in Porcine Serum–Induced Rat Liver Fibrosis
Bhunchet, E., & Wake, K. (1992) · Hepatology · doi:10.1002/hep.1840160623 · Cited by 128 · see citing works
Smart, D. E., Vincent, K. J., Arthur, M. J. P., Eickelberg, O., Castellazzi, M., Mann, J., & Mann, D. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101840200 · Cited by 97 · see citing works
del Castillo‐Olivares, A., & Gil, G. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.19.4035 · Cited by 88 · see citing works
Bahr, M. J., Vincent, K. J., Arthur, M. J. P., Fowler, A. V., Smart, D. E., Wright, M. C., Clark, I. M., Benyon, C. R., Iredale, J. P., & Mann, D. A. (1999) · Hepatology · doi:10.1002/hep.510290333 · Cited by 82 · see citing works
Estrogen Receptor α Regulates Expression of the Orphan Receptor Small Heterodimer Partner
Lai, K., Harnish, D. C., & Evans, M. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303913200 · Cited by 81 · see citing works
Sakaida, I., Uchida, K., Matsumura, Y., & Okita, K. (1998) · Journal of Hepatology · doi:10.1016/s0168-8278(98)80322-x · Cited by 52 · see citing works
Matsumura, Y., Saikaida, I., Uchida, K., Kimura, T., Ishihara, T., & Okita, K. (1997) · Journal of Hepatology · doi:10.1016/s0168-8278(97)80300-5 · Cited by 52 · see citing works
Lee, Y. J., Aroor, A. R., & Shukla, S. D. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.301.3.908 · Cited by 50 · see citing works
Transcriptional Regulation in Hepatic Stellate Cells
Eng, F. J., & Friedman, S. L. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-17553 · Cited by 44 · see citing works
Inoue, H., Iguch, H., Kouno, A., et al. (2001) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(01)00162-1 · Cited by 30 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Mann DA, Smart DE. Transcriptional regulation of hepatic stellate cell activation. Gut 2002;50:891-896.
- Bhunchet E, Wake K. Role of mesenchymal cell proliferation in PS-induced rat liver fibrosis. Hepatology 1992;16:1452-1472.
- Sakaida I, Uchida K, Matsumura Y, Okita K. Interferon ␥ treat- ment prevents procollagen gene expression without affecting TGF-1 expression in pig serum-induced rat liver fibrosis in vivo. J Hepatol 1998;28:471-479.
Cited by
Sorted by citations
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842 · see citing works
Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280 · see citing works
Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)33041-7 · Cited by 1,277 · see citing works
Mudaliar, S., Henry, R. R., Sanyal, A. J., Morrow, L., Marschall, H., Kipnes, M., Adorini, L., Sciacca, C. I., Clopton, P., Castelloe, E., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.05.042 · Cited by 931 · see citing works
Bile acid receptors as targets for drug development
Schaap, F. G., Trauner, M., & Jansen, P. L. M. (2014) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.151 · Cited by 696 · see citing works
Bile acid nuclear receptor FXR and digestive system diseases
Ding, L., Yang, L., Wang, Z., & Huang, W. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.01.004 · Cited by 477 · see citing works
Metabolic reprogramming in liver fibrosis
Horn, P., & Tacke, F. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.05.003 · Cited by 432 · see citing works
FXR: a metabolic regulator and cell protector
Wang, Y.-D., Chen, W.-D., Moore, D. D., & Huang, W. (2008) · Cell Research · doi:10.1038/cr.2008.289 · Cited by 389 · see citing works
Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice
Kim, I., Morimura, K., Shah, Y., Yang, Q., Ward, J. M., & Gonzalez, F. J. (2007) · Carcinogenesis · doi:10.1093/carcin/bgl249 · Cited by 357 · see citing works
FXR, a multipurpose nuclear receptor
Lee, F. Y., Lee, H., Hubbert, M. L., Edwards, P. A., & Zhang, Y. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.08.002 · Cited by 344 · see citing works
Hepatic fibrosis: molecular mechanisms and drug targets
Lotersztajn, S., Julien, B., Teixeira-Clerc, F., Grenard, P., & Mallat, A. (2005) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095906 · Cited by 325 · see citing works
Zhang, S., Wang, J., Liu, Q., & Harnish, D. C. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.025 · Cited by 290 · see citing works
Pathogenesis of cholestatic liver disease and therapeutic approaches
Hirschfield, G. M., Heathcote, E. J., & Gershwin, M. E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.09.004 · Cited by 287 · see citing works
A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis
Kowdley, K. V., Luketic, V., Chapman, R., Hirschfield, G. M., Poupon, R., Schramm, C., Vincent, C., Rust, C., Parés, A., Mason, A., et al. (2018) · Hepatology · doi:10.1002/hep.29569 · Cited by 281 · see citing works
Verbeke, L., Farre, R., Trebicka, J., Komuta, M., Roskams, T., Klein, S., Elst, I. V., Windmolders, P., Vanuytsel, T., Nevens, F., et al. (2014) · Hepatology · doi:10.1002/hep.26939 · Cited by 258 · see citing works
Verbeke, L., Mannaerts, I., Schierwagen, R., Govaere, O., Klein, S., Vander Elst, I., Windmolders, P., Farre, R., Wenes, M., Mazzone, M., et al. (2016) · Scientific Reports · doi:10.1038/srep33453 · Cited by 236 · see citing works
Metabolic Messengers: bile acids
Perino, A., & Schoonjans, K. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00559-z · Cited by 223 · see citing works
Fiorucci, S., Rizzo, G., Antonelli, E., Renga, B., Mencarelli, A., Riccardi, L., Orlandi, S., Pruzanski, M., Morelli, A., & Pellicciari, R. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.084905 · Cited by 183 · see citing works
Self-citationTrauner, M., Nevens, F., Shiffman, M. L., Drenth, J. P. H., Bowlus, C. L., Vargas, V., Andreone, P., Hirschfield, G. M., Pencek, R., Malecha, E. S., et al. (2019) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(19)30094-9 · Cited by 180 · see citing works
Úbeda, M., Lario, M., Muñoz, L., Borrero, M.-J., Rodríguez-Serrano, M., Sánchez-Díaz, A.-M., del Campo, R., Lledó, L., Pastor, Ó., García-Bermejo, L., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2015.12.010 · Cited by 178 · see citing works
Mencarelli, A., Renga, B., Migliorati, M., Cipriani, S., Distrutti, E., Santucci, L., & Fiorucci, S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901347 · Cited by 177 · see citing works
Schwabl, P., Hambruch, E., Seeland, B. A., Hayden, H., Wagner, M., Garnys, L., Strobel, B., Schubert, T.-L., Riedl, F., Mitteregger, D., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2016.12.005 · Cited by 178 · see citing works
Fiorucci, S., Rizzo, G., Antonelli, E., Renga, B., Mencarelli, A., Riccardi, L., Morelli, A., Pruzanski, M., & Pellicciari, R. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.085597 · Cited by 177 · see citing works
Self-citationFickert, P., Fuchsbichler, A., Moustafa, T., Wagner, M., Zollner, G., Halilbasic, E., Stöger, U., Arrese, M., Pizarro, M., Solís, N., et al. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.090114 · Cited by 169 · see citing works
SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis
Zhou, J., Cui, S., He, Q., Guo, Y., Pan, X., Zhang, P., Huang, N., Ge, C., Wang, G., Gonzalez, F. J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14138-6 · Cited by 154 · see citing works
Nuclear receptors as therapeutic targets in cholestatic liver diseases
Zollner, G., & Trauner, M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00030.x · Cited by 146 · see citing works
Beaven, S. W., Wroblewski, K., Wang, J., Hong, C., Bensinger, S., Tsukamoto, H., & Tontonoz, P. (2011) · Gastroenterology · doi:10.1053/j.gastro.2010.11.053 · Cited by 131 · see citing works
Transcriptional regulation of hepatic stellate cells
Mann, J., & Mann, D. A. (2009) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2009.03.011 · Cited by 119 · see citing works
Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis
Zhou, J., Huang, N., Guo, Y., Cui, S., Ge, C., He, Q., Pan, X., Wang, G., Wang, H., & Hao, H. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2018.11.004 · Cited by 99 · see citing works
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Li, J., Zhang, Y., Kuruba, R., Gao, X., Gandhi, C. R., Xie, W., & Li, S. (2011) · Molecular Pharmacology · doi:10.1124/mol.110.068247 · Cited by 78 · see citing works
Role of bile acids in the regulation of the metabolic pathways
Taoka, H., Yokoyama, Y., Morimoto, K., Kitamura, N., Tanigaki, T., Takashina, Y., Tsubota, K., & Watanabe, M. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i13.260 · Cited by 80 · see citing works
Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand
Li, J., Kuruba, R., Wilson, A., Gao, X., Zhang, Y., & Li, S. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013955 · Cited by 66 · see citing works
Renga, B., Mencarelli, A., Migliorati, M., Cipriani, S., D’Amore, C., Distrutti, E., & Fiorucci, S. (2011) · Inflammation Research · doi:10.1007/s00011-010-0306-1 · Cited by 53 · see citing works
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Venetsanaki, V., Karabouta, Z., & Polyzos, S. A. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172661 · Cited by 52 · see citing works
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Königshofer, P., Brusilovskaya, K., Petrenko, O., Hofer, B. S., Schwabl, P., Trauner, M., & Reiberger, T. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166235 · Cited by 45 · see citing works
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Floreani, A., Gabbia, D., & De Martin, S. (2022) · Biomedicines · doi:10.3390/biomedicines10102464 · Cited by 41 · see citing works
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Brusilovskaya, K., Königshofer, P., Schwabl, P., & Reiberger, T. (2019) · Seminars in Liver Disease · doi:10.1055/s-0039-1693115 · Cited by 28 · see citing works
Cipriani, S., Carino, A., Masullo, D., Zampella, A., Distrutti, E., & Fiorucci, S. (2017) · Scientific Reports · doi:10.1038/srep41055 · Cited by 16 · see citing works
Self-citationAzizsoltani, A., Niknam, B., Taghizadeh-Teymorloei, M., Ghoodjani, E., Dianat-Moghadam, H., & Alizadeh, E. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118249 · Cited by 15 · see citing works
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Liu, C.-H., & Bowlus, C. L. (2022) · Clinics in Liver Disease · doi:10.1016/j.cld.2022.06.012 · Cited by 9 · see citing works
- Authors
- Fiorucci, S., Antonelli, E., Rizzo, G., Renga, B., Mencarelli, A., Riccardi, L., Orlandi, S., Pellicciari, R., & Morelli, A.
- Affiliations
- University of Perugia (IT)
- Corresponding author
- Fiorucci, Stefano
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2004-11
- Volume
- 127
- Issue
- 5
- Pages
- 1497-1512
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1970740746
- Cited by
- 472
- References
- 51
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 22 · 2023: 19 · 2022: 24 · 2021: 27 · 2020: 20 · 2019: 30 · 2018: 25 · 2017: 24 · 2016: 26 · 2015: 27 · 2014: 25 · 2013: 14 · 2012: 24
- FWCI
- 9.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Intercept Pharmaceuticals
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- farnesoid X receptor, small heterodimer partner, hepatic stellate cells, liver fibrosis, bile acids, type I collagen, TGF-β1, alpha-smooth muscle actin, TIMP-1, TIMP-2, thrombin, JunD, AP-1, bile duct ligation, antifibrotic therapy
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Chenodeoxycholic Acid, Cloning, Molecular, DNA-Binding Proteins, Hydroxyproline, Liver, Liver Cirrhosis, Experimental, Male, Swine, Transcription Factors, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Rats
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