Increased production of sonic hedgehog by ballooned hepatocytes
Open accessAbstract
Ballooned hepatocytes distinguish non‐alcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases the risk for fibrosis in NASH, suggesting that ballooned hepatocytes release pro‐fibrogenic factors. Hedgehog ligands function as pro‐fibrogenic factors in liver diseases, but mechanisms for hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro‐fibrogenic signals to neighbouring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18‐negative/ubiquitin‐positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro , primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin‐treated hepatocytes increased Gli‐luciferase reporter activity 14‐fold more than conditioned medium from vehicle‐treated hepatocytes. Cyclopamine (hedgehog signalling inhibitor) abrogated the effect of conditioned medium from tunicamycin‐treated hepatocytes, verifying that soluble hepatocyte‐derived factors activate hedgehog signalling. Ballooned hepatocytes in NASH patients did not express the hedgehog target gene, Gli2 , α‐smooth muscle actin or vimentin, but were surrounded by Gli2 ‐positive stromal cells expressing these myofibroblast markers. Trichrome staining demonstrated the accumulation of ballooned hepatocytes in areas of matrix deposition, and numbers of Sonic hedgehog‐positive hepatocytes correlated with the degree of ballooning and fibrosis stage. Hepatocytes undergoing endoplasmic reticiulum stress generate hedgehog ligands which act as paracrine pro‐fibrogenic factors for hedgehog‐responsive stromal cells. These results help to explain why fibrosis stage correlates with hepatocyte ballooning in NASH. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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
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?
Hedgehog pathway activation is triggered by injured, ballooned and/or TAZ-expressing hepatocytes in NASH via the release of sonic hedgehog or Indian hedgehog.
“Hedgehog pathway activation is triggered by injured, ballooned and/or TAZ-expressing hepatocytes in NASH via the release of sonic hedgehog or Indian hedgehog.30,38”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [38]
Hedgehog pathways including Indian hedgehog and sonic hedgehog are expressed in ballooned NASH hepatocytes and closely correlate with lymphocytic infiltration, ductular reaction and ECM collagen deposition.
“hedgehog pathways including Indian hedgehog and sonic hedgehog, which are expressed in ballooned NASH hepatocytes and closely correlate with lymphocytic infiltration, ductular reaction and ECM collagen deposition.38”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [38]
These signals include sonic hedgehog, which activates hedgehog signaling in surrounding stromal cells.
“These signals include sonic hedgehog, which activates hedgehog signaling in the surrounding stromal cells (157).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [157]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y., Torbenson, M. S., Unalp‐Arida, A., et al. (2005) · Hepatology · doi:10.1002/hep.20701 · Cited by 10,791 · see citing works
Nonalcoholic Fatty Liver Disease
Angulo, P. (2002) · New England Journal of Medicine · doi:10.1056/nejmra011775 · Cited by 5,228 · see citing works
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
MATTEONI, C., YOUNOSSI, Z., GRAMLICH, T., BOPARAI, N., LIU, Y., & MCCULLOUGH, A. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70506-8 · Cited by 3,345 · see citing works
Nonalcoholic fatty liver disease
Adams, L. A. (2005) · Canadian Medical Association Journal · doi:10.1503/cmaj.045232 · Cited by 1,652 · see citing works
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis
Feldstein, A. E., Canbay, A., Angulo, P., Taniai, M., Burgart, L. J., Lindor, K. D., & Gores, G. J. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00907-7 · Cited by 1,085 · see citing works
Activation and Dysregulation of the Unfolded Protein Response in Nonalcoholic Fatty Liver Disease
Puri, P., Mirshahi, F., Cheung, O., Natarajan, R., Maher, J. W., Kellum, J. M., & Sanyal, A. J. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.10.039 · Cited by 596 · see citing works
Alpha 1 -Antitrypsin Deficiency — A Model for Conformational Diseases
Carrell, R. W., & Lomas, D. A. (2002) · New England Journal of Medicine · doi:10.1056/nejmra010772 · Cited by 447 · see citing works
From Mallory to Mallory–Denk bodies: What, how and why?
Zatloukal, K., French, S. W., Stumptner, C., Strnad, P., Harada, M., Toivola, D. M., Cadrin, M., & Omary, M. B. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.04.024 · Cited by 341 · see citing works
Toward unraveling the complexity of simple epithelial keratins in human disease
Omary, M. B., Ku, N., Strnad, P., & Hanada, S. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37762 · Cited by 267 · see citing works
Syn, W., Jung, Y., Omenetti, A., Abdelmalek, M. F., Guy, C. D., Yang, L., Wang, J., Witek, R. P., Fearing, C. M., Pereira, T. A., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.06.051 · Cited by 257 · see citing works
Self-citationHepatocellular ballooning in NASH
Caldwell, S. H., Ikura, Y., Dias, D., Isomoto, K., Yabu, A., Moskaluk, C. A., Pramoonjago, P., Simmons, W., Scruggs, H., Rosenbaum, N., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.04.031 · Cited by 244 · see citing works
Ballooned hepatocytes in steatohepatitis: The value of keratin immunohistochemistry for diagnosis
Lackner, C., Gogg-Kamerer, M., Zatloukal, K., Stumptner, C., Brunt, E. M., & Denk, H. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.01.026 · Cited by 240 · see citing works
Choi, S. S., Omenetti, A., Witek, R. P., Moylan, C. A., Syn, W.-K., Jung, Y., Yang, L., Sudan, D. L., Sicklick, J. K., Michelotti, G. A., et al. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00292.2009 · Cited by 219 · see citing works
Self-citationHedgehog signaling maintains resident hepatic progenitors throughout life
Sicklick, J. K., Li, Y.-X., Melhem, A., Schmelzer, E., Zdanowicz, M., Huang, J., Caballero, M., Fair, J. H., Ludlow, J. W., McClelland, R., et al. (2005) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00456.2005 · Cited by 212 · see citing works
Self-citationWitek, R. P., Yang, L., Liu, R., Jung, Y., Omenetti, A., Syn, W., Choi, S. S., Cheong, Y., Fearing, C. M., Agboola, K. M., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.09.066 · Cited by 210 · see citing works
Self-citationLiver Disease in Alpha 1-Antitrypsin Deficiency: A Review
Fairbanks, K. D., & Tavill, A. S. (2008) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2008.01955.x · Cited by 210 · see citing works
Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells
Yang, L., Wang, Y., Mao, H., Fleig, S. V., Omenetti, A., Brown, K. D., Sicklick, J. K., Li, Y., & Diehl, A. M. (2007) · Journal of Hepatology · doi:10.1016/j.jhep.2007.07.032 · Cited by 200 · see citing works
Self-citationHedgehog Signaling Is Critical for Normal Liver Regeneration After Partial Hepatectomy in Mice
Ochoa, B., Syn, W., Delgado, I., Karaca, G., Jung, Y., Wang, J., Zubiaga, A. M., Fresnedo, O., Omenetti, A., Zdanowicz, M., et al. (2010) · Hepatology · doi:10.1002/hep.23525 · Cited by 188 · see citing works
Self-citationChoi, S. S., Syn, W., Karaca, G., Omenetti, A., Moylan, C. A., Witek, R. P., Agboola, K. M., Jung, Y., Michelotti, G. A., & Diehl, A. M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.168542 · Cited by 174 · see citing works
Self-citationOmenetti, A., Yang, L., Li, Y., McCall, S. J., Jung, Y., Sicklick, J. K., Huang, J., Choi, S. S., Suzuki, A., & Diehl, A. M. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700537 · Cited by 173 · see citing works
Self-citationHistopathology of Non-Alcoholic Fatty Liver Disease
Brunt, E. M. (2009) · Clinics in Liver Disease · doi:10.1016/j.cld.2009.07.008 · Cited by 170 · see citing works
Jung, Y., Brown, K. D., Witek, R. P., Omenetti, A., Yang, L., Vandongen, M., Milton, R. J., Hines, I. N., Rippe, R. A., Spahr, L., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.02.022 · Cited by 167 · see citing works
Self-citationSignals from dying hepatocytes trigger growth of liver progenitors
Jung, Y., Witek, R. P., Syn, W., Choi, S. S., Omenetti, A., Premont, R. T., Guy, C. D., & Diehl, A. M. (2010) · Gut · doi:10.1136/gut.2009.204354 · Cited by 161 · see citing works
Self-citationYang, S., Koteish, A. A., Lin, H., Huang, J., Roskams, T., Dawson, V. L., & Diehl, A. M. (2004) · Hepatology · doi:10.1002/hep.20082 · Cited by 150 · see citing works
Self-citationPathologic features associated with fibrosis in nonalcoholic fatty liver disease
Gramlich, T. L., Kleiner, D. E., McCullough, A. J., Matteoni, C. A., Boparai, N., & Younossi, Z. M. (2004) · Human Pathology · doi:10.1016/j.humpath.2003.09.018 · Cited by 143 · see citing works
In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C
Asselah, T., Bièche, I., Mansouri, A., Laurendeau, I., Cazals-Hatem, D. L., Feldmann, G., Bédossa, P., Paradis, V., Martinot-Peignoux, M., Lebrec, D., et al. (2010) · The Journal of Pathology · doi:10.1002/path.2703 · Cited by 127 · see citing works
Cytoskeletal keratin glycosylation protects epithelial tissue from injury
Ku, N., Toivola, D. M., Strnad, P., & Omary, M. B. (2010) · Nature Cell Biology · doi:10.1038/ncb2091 · Cited by 121 · see citing works
Sonic Hedgehog Protects Cortical Neurons Against Oxidative Stress
Dai, R., Zhu, S.-Y., Xia, Y., Mao, L., Mei, Y.-W., Yao, Y., Xue, Y.-M., & Hu, B. (2010) · Neurochemical Research · doi:10.1007/s11064-010-0264-6 · Cited by 115 · see citing works
Mallory–Denk-bodies: Lessons from keratin-containing hepatic inclusion bodies
Strnad, P., Zatloukal, K., Stumptner, C., Kulaksiz, H., & Denk, H. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.08.008 · Cited by 114 · see citing works
Pereira, T. A., Witek, R. P., Syn, W., Choi, S. S., Bradrick, S. S., Karaca, G., Agboola, K. M., Jung, Y., Omenetti, A., Moylan, C. A., et al. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2010.147 · Cited by 114 · see citing works
Self-citationEndoplasmic Reticulum Stress and the Unfolded Protein Response
Kapoor, A., & Sanyal, A. J. (2009) · Clinics in Liver Disease · doi:10.1016/j.cld.2009.07.004 · Cited by 111 · see citing works
Omenetti, A., & Diehl, A. M. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00543.2007 · Cited by 109 · see citing works
Self-citationFleig, S. V., Choi, S. S., Yang, L., Jung, Y., Omenetti, A., VanDongen, H. M. A., Huang, J., Sicklick, J. K., & Diehl, A. M. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700689 · Cited by 85 · see citing works
Self-citationBussche, A. V. D., Machida, R., Li, K., Loevinsohn, G. S., Khander, A., Wang, J., Wakita, T., Wands, J. R., & Li, J. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.05.022 · Cited by 51 · see citing works
Non-Alcoholic Steatohepatitis Pathogenesis: Role of Repair in Regulating the Disease Progression
Jung, Y., & Diehl, A. M. (2010) · Digestive Diseases · doi:10.1159/000282092 · Cited by 26 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis
Diehl, A. M., & Day, C. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1503519 · Cited by 1,283 · see citing works
Self-citationEASL Clinical Practice Guidelines: Management of alcohol-related liver disease
Thursz, M. R., Gual, A., Lackner, C., Mathurin, P., Moreno, C., Spahr, L., Sterneck, M. R., & Cortez‐Pinto, H. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.03.018 · Cited by 953 · see citing works
Lipotoxicity and the gut-liver axis in NASH pathogenesis
Marra, F., & Svegliati-Baroni, G. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.11.014 · Cited by 847 · see citing works
Nonalcoholic fatty liver disease
Brunt, E., Wong, V., Nobili, V., Day, C., Sookoian, S., Maher, J., Bugianesi, E., Sirlin, C., Neuschwander-Tetri, B., & Rinella, M. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.80 · Cited by 591 · see citing works
Hepatic inflammatory responses in liver fibrosis
Hammerich, L., & Tacke, F. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00807-x · Cited by 803 · see citing works
Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Schwabe, R. F., Tabas, I., & Pajvani, U. B. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.311 · Cited by 671 · see citing works
Pathogenesis of Nonalcoholic Steatohepatitis
Machado, M. V., & Diehl, A. M. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.066 · Cited by 541 · see citing works
Self-citationNASH is an Infl ammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications
Farrell, G. C., Rooyen, D. M. V., Gan, L. T., & Chitturi, S. (2012) · Gut and Liver · doi:10.5009/gnl.2012.6.2.149 · Cited by 396 · see citing works
Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation
Peverill, W., Powell, L. W., & Skoien, R. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15058591 · Cited by 380 · see citing works
Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis
Yang, J. D., Abdelmalek, M. F., Pang, H., Guy, C. D., Smith, A. D., Diehl, A. M., & Suzuki, A. (2014) · Hepatology · doi:10.1002/hep.26761 · Cited by 374 · see citing works
Self-citationRole of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease
Hammoutene, A., & Rautou, P.-E. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.02.012 · Cited by 364 · see citing works
Kumar, S., Duan, Q., Wu, R., Harris, E. N., & Su, Q. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113869 · Cited by 355 · see citing works
Fibrosis and alcohol-related liver disease
Lackner, C., & TINIAKOS, D. G. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.12.003 · Cited by 326 · see citing works
Lackner, C., Spindelboeck, W., Haybaeck, J., Douschan, P., Rainer, F., Terracciano, L., Haas, J. G., Berghold, A., Bataller, R. A., & Stauber, R. E. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.11.011 · Cited by 294 · see citing works
Suppli, M. P., Rigbolt, K. T. G., Veidal, S. S., Heebøll, S., Eriksen, P. L., Demant, M., Bagger, J. I., Nielsen, J. C., Oró, D., Thrane, S. W., et al. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00358.2018 · Cited by 288 · see citing works
Ibrahim, S. H., Hirsova, P., & Gores, G. J. (2018) · Gut · doi:10.1136/gutjnl-2017-315691 · Cited by 278 · see citing works
Hedgehog signaling in the liver
Omenetti, A., Choi, S. S., Michelotti, G. A., & Diehl, A. M. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.10.003 · Cited by 278 · see citing works
Self-citationLiver zonation: Novel aspects of its regulation and its impact on homeostasis
Gebhardt, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i26.8491 · Cited by 275 · see citing works
Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis
Hirsova, P., Ibrabim, S. H., Gores, G. J., & Malhi, H. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r066357 · Cited by 270 · see citing works
Features, Diagnosis, and Treatment of Nonalcoholic Fatty Liver Disease
Torres, D. M., Williams, C. D., & Harrison, S. A. (2012) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2012.03.011 · Cited by 269 · see citing works
Hyun, J., Wang, S., Kim, J., Rao, K. M., Park, S. Y., Chung, I., Ha, C., Kim, S., Yun, Y., & Jung, Y. (2016) · Nature Communications · doi:10.1038/ncomms10993 · Cited by 219 · see citing works
Guy, C. D., Suzuki, A., Zdanowicz, M., Abdelmalek, M. F., Burchette, J. L., Ünalp, A., & Diehl, A. M. (2011) · Hepatology · doi:10.1002/hep.25559 · Cited by 217 · see citing works
Self-citationYilmaz, Y. N. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12046 · Cited by 217 · see citing works
Tillman, E. J., & Rolph, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601290 · Cited by 209 · see citing works
Choi, H. S. J., Brouwer, W. P., Zanjir, W. M. R., de Man, R. A., Feld, J. J., Hansen, B. E., Janssen, H. L. A., & Patel, K. (2020) · Hepatology · doi:10.1002/hep.30857 · Cited by 211 · see citing works
Non-alcoholic fatty liver disease: What the clinician needs to know
Machado, M. V. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i36.12956 · Cited by 209 · see citing works
Farrell, G. C., Haczeyni, F., & Chitturi, S. (2018) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-10-8684-7_3 · Cited by 178 · see citing works
Pathophysiological mechanisms underlying MAFLD
Kuchay, M. S., Choudhary, N. S., & Mishra, S. K. (2020) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2020.09.026 · Cited by 180 · see citing works
A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence
Temple, J., Cordero, P., Li, J., Nguyen, V., & Oben, J. A. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060947 · Cited by 171 · see citing works
Philips, G., Chan, I. S., Swiderska, M., Schroder, V. T., Guy, C. D., Karaca, G., Moylan, C. A., Venkatraman, T. N., Feuerlein, S., Syn, W., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023943 · Cited by 164 · see citing works
Self-citationSuzuki, A., & Diehl, A. M. (2016) · Annual Review of Medicine · doi:10.1146/annurev-med-051215-031109 · Cited by 159 · see citing works
Self-citationFound in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158 · see citing works
Diagnosis and Assessment of NAFLD: Definitions and Histopathological Classification
Lackner, C., TINIAKOS, D. G., & Burt, A. D. (2015) · Seminars in Liver Disease · doi:10.1055/s-0035-1562942 · Cited by 145 · see citing works
Hyun, J., Wang, S., Kim, J., Kim, G. J., & Jung, Y. (2015) · Scientific Reports · doi:10.1038/srep14135 · Cited by 135 · see citing works
Signals and Cells Involved in Regulating Liver Regeneration
Kang, L., Mars, W. M., & Michalopoulos, G. K. (2012) · Cells · doi:10.3390/cells1041261 · Cited by 134 · see citing works
MicroRNAs in the pathogenesis and treatment of progressive liver injury in NAFLD and liver fibrosis
Su, Q., Kumar, V., Sud, N., & Mahato, R. I. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.01.009 · Cited by 127 · see citing works
Chung, S. I., Moon, H., Ju, H.-L., Cho, K. J., Kim, D. Y., Han, K., Eun, J. W., Nam, S. W., Ribback, S., Dombrowski, F., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.10.007 · Cited by 115 · see citing works
Understanding the cellular interactome of non-alcoholic fatty liver disease
Wallace, S. J., Tacke, F., Schwabe, R. F., & Henderson, N. C. (2022) · JHEP Reports · doi:10.1016/j.jhepr.2022.100524 · Cited by 116 · see citing works
Recent insights into the molecular pathophysiology of lipid droplet formation in hepatocytes
Sahini, N., & Borlak, J. T. (2014) · Progress in Lipid Research · doi:10.1016/j.plipres.2014.02.002 · Cited by 114 · see citing works
Alcohol-related liver disease: Areas of consensus, unmet needs and opportunities for further study
Thursz, M. R., Kamath, P. S., Mathurin, P., Szabó, G., & Shah, V. H. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.10.041 · Cited by 112 · see citing works
Szabó, G., Kamath, P. S., Shah, V. H., Thursz, M. R., Mathurin, P., Addolorato, G., Bataller, R. A., Burra, P., Castéra, L., Cortez‐Pinto, H., et al. (2019) · Hepatology · doi:10.1002/hep.30369 · Cited by 108 · see citing works
Self-citationMachado, M. V., Michelotti, G. A., Pereira, T. A., Boursier, J., Krüger, L., Swiderska‐Syn, M., Karaca, G., Xie, G., Guy, C. D., Bohinc, B. N., et al. (2014) · Gut · doi:10.1136/gutjnl-2014-307362 · Cited by 102 · see citing works
Self-citationMao, X., Cheung, K. S., Peng, C., Mak, L., Cheng, H. M., Fung, J., Peleg, N., Leung, H. H. W., Kumar, R., Lee, J., et al. (2022) · Hepatology · doi:10.1002/hep.32792 · Cited by 100 · see citing works
Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease
Kuchay, M. S., Choudhary, N. S., & Ramos‐Molina, B. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00951.2024 · Cited by 97 · see citing works
Yang, J. D., Abdelmalek, M. F., Guy, C. D., Gill, R. M., Lavine, J. E., Yates, K. P., Klair, J. S., Terrault, N. A., Clark, J. M., Ünalp–Arida, A., et al. (2016) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2016.07.034 · Cited by 93 · see citing works
Self-citationOsteopontin: Versatile modulator of liver diseases
Nagoshi, S. (2013) · Hepatology Research · doi:10.1111/hepr.12166 · Cited by 87 · see citing works
Vismodegib Suppresses TRAIL-mediated Liver Injury in a Mouse Model of Nonalcoholic Steatohepatitis
Hirsova, P., Ibrahim, S. H., Bronk, S. F., Yagita∥, H., & Gores, G. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070599 · Cited by 86 · see citing works
Kwon, H., Song, K., Han, C. L., Chen, W., Wang, Y., Dash, S., Lim, K., & Wu, T. (2015) · Hepatology · doi:10.1002/hep.28289 · Cited by 86 · see citing works
Self-citationGrzelak, C. A., Martelotto, L. G., Sigglekow, N. D., Patkunanathan, B., Ajami, K., Calabrò, S., Dwyer, B. J., Tirnitz‐Parker, J. E. E., Watkins, D. N., Warner, F. J., et al. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.08.012 · Cited by 82 · see citing works
Role of canonical Hedgehog signaling pathway in liver
Gao, L., Zhang, Z., Zhang, P., Yu, M., & Yang, T. (2018) · International Journal of Biological Sciences · doi:10.7150/ijbs.28089 · Cited by 80 · see citing works
Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease
Wiering, L., Subramanian, P., & Hammerich, L. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.02.010 · Cited by 80 · see citing works
Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity
Guy, C. D., Suzuki, A., Abdelmalek, M. F., Burchette, J. L., Diehl, A. M., & CRN, F. T. N. (2015) · Hepatology · doi:10.1002/hep.27235 · Cited by 72 · see citing works
Self-citationNon-alcoholic fatty liver disease: the pathologist’s perspective
Leow, W. Q., Chan, A. W. H., Mendoza, P. G. L., Lo, R. C., Yap, K., & Kim, H. (2022) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0329 · Cited by 70 · see citing works
Ding, J., Li, H., Zhang, L., Zhou, Y., & Wu, J. H. (2021) · Cells · doi:10.3390/cells10010123 · Cited by 64 · see citing works
A hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes
Kakisaka, K., Cazanave, S. C., Werneburg, N. W., Razumilava, N., Mertens, J. C., Bronk, S. F., & Gores, G. J. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.05.011 · Cited by 65 · see citing works
Hedgehog pathway and pediatric nonalcoholic fatty liver disease
Swiderska‐Syn, M., Suzuki, A., Guy, C. D., Schwimmer, J. B., Abdelmalek, M. F., Lavine, J. E., & Diehl, A. M. (2013) · Hepatology · doi:10.1002/hep.26230 · Cited by 63 · see citing works
Self-citationMechanisms of Disease Progression in NASH
Bohinc, B. N., & Diehl, A. M. (2012) · Clinics in Liver Disease · doi:10.1016/j.cld.2012.05.002 · Cited by 62 · see citing works
Self-citationEnvisioning how to advance the MASH field
Allen, A. M., Younossi, Z. M., Diehl, A. M., Charlton, M., & Lazarus, J. V. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00938-9 · Cited by 63 · see citing works
Self-citationHepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levels
Matz-Soja, M., Aleithe, S., Marbach, E., Böttger, J., Arnold, K., Schmidt-Heck, W., Kratzsch, J., & Gebhardt, R. (2014) · Cell Communication and Signaling · doi:10.1186/1478-811x-12-11 · Cited by 60 · see citing works
Nascimbeni, F., Ballestri, S., Machado, M. V., Mantovani, A., Cortez‐Pinto, H., Targher, G., & Lonardo, A. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2018.1415756 · Cited by 60 · see citing works
Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease
Baffy, G. (2018) · Digestive Diseases and Sciences · doi:10.1007/s10620-017-4903-5 · Cited by 61 · see citing works
Sonic hedgehog signaling in kidney fibrosis: a master communicator
Zhou, D. F., Tan, R. J., & Liu, Y. (2016) · Science China Life Sciences · doi:10.1007/s11427-016-0020-y · Cited by 58 · see citing works
Niu, X., Jiang, X., Xu, G.-D., Zheng, G.-M., Tang, Z., Yin, N., Li, X.-Q., Yang, Y.-Y., & Lv, P.-Y. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27332 · Cited by 56 · see citing works
Paracrine Hedgehog Signaling Drives Metabolic Changes in Hepatocellular Carcinoma
Chan, I. S., Guy, C. D., Chen, Y., Lü, J., Swiderska‐Syn, M., Michelotti, G. A., Karaca, G., Xie, G., Krüger, L., Syn, W., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1068 · Cited by 56 · see citing works
Self-citationHepatocytic ballooning in non‐alcoholic steatohepatitis: Dilemmas and future directions
Li, Y., Zheng, T., Xiao, S., Wang, P., Yang, W., Jiang, L., Chen, L., Sha, J., Jin, Y., Chen, S., et al. (2023) · Liver International · doi:10.1111/liv.15571 · Cited by 53 · see citing works
The hedgehog pathway in nonalcoholic fatty liver disease
Machado, M. V., & Diehl, A. M. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1448752 · Cited by 52 · see citing works
Self-citationPerspectives on NASH Histology: Cellular Ballooning
Caldwell, S. H., & Lackner, C. (2017) · Annals of Hepatology · doi:10.5604/16652681.1231562 · Cited by 51 · see citing works
Shen, X., Peng, Y., & Li, H. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01450 · Cited by 51 · see citing works
Lee, C., Kim, J., Wang, S., Sung, S., Kim, N., Lee, H., Seo, Y., & Jung, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092369 · Cited by 51 · see citing works
Kostallari, E., & Shah, V. H. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-11093-2_9 · Cited by 49 · see citing works
Kim, M. N., Han, K., Yoo, J., Hwang, S. G., & Ahn, S. H. (2021) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.16706 · Cited by 48 · see citing works
Potential Role of Hedgehog Pathway in Liver Response to Radiation
Wang, S., Lee, Y. J., Kim, J., Hyun, J., Lee, K., Kim, Y.-H., & Jung, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074141 · Cited by 48 · see citing works
NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease
Li, Y., Chen, M., Zhou, Y., Tang, C., Zhang, W., Zhong, Y., Chen, Y., Zhou, H. Y., & Sheng, L. (2020) · Theranostics · doi:10.7150/thno.40149 · Cited by 47 · see citing works
Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease
Schwabe, R. F., Tacke, F., Sugimoto, A., & Friedman, S. L. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2025.101421 · Cited by 50 · see citing works
Epigenetic regulation of the Hedgehog and Wnt pathways in cancer.
Wils, L., & Bijlsma, M. (2018) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2017.11.013 · Cited by 43 · see citing works
Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System
Torre, P., Motta, B., Sciorio, R., Masarone, M., & Persico, M. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.781567 · Cited by 41 · see citing works
The Role of Liver Zonation in Physiology, Regeneration, and Disease
Panday, R., Monckton, C. P., & Khetani, S. R. (2022) · Seminars in Liver Disease · doi:10.1055/s-0041-1742279 · Cited by 44 · see citing works
Nonalcoholic fatty liver disease: Current therapies and future perspectives in drug delivery
Domingues, I., Leclercq, I. A., & Beloqui, A. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.09.040 · Cited by 44 · see citing works
Ando, S., Shibahara, J., Hayashi, A., & Fukayama, M. (2015) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-015-1836-2 · Cited by 42 · see citing works
Role of Hedgehog Signaling Pathway in NASH
Machado, M. V., & Diehl, A. M. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060857 · Cited by 42 · see citing works
Self-citationHirsova, P., & Gores, G. J. (2014) · Hepatology · doi:10.1002/hep.27279 · Cited by 40 · see citing works
Rodrigues, S. G., Montani, M., Guixé‐Muntet, S., Gottardi, A. D., Berzigotti, A., & Bosch, J. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.12.038 · Cited by 38 · see citing works
El-Derany, M. O., & El‐Demerdash, E. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113942 · Cited by 36 · see citing works
Wang, S., Kim, J., Lee, C., Oh, D., Han, J., Kim, T., Kim, S. W., Seo, Y., Oh, S., & Jung, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119375 · Cited by 34 · see citing works
Chu, J., Yan, R., Wang, S., Li, G., Kang, X., Hu, Y. W., Lin, M., Shan, W., Zhao, Y., Wang, Z., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.668708 · Cited by 34 · see citing works
Matz‐Soja, M., Hovhannisyan, A., & Gebhardt, R. (2013) · Medical Hypotheses · doi:10.1016/j.mehy.2013.01.032 · Cited by 34 · see citing works
Hedgehog Signaling Regulates the Repair Response in Mouse Liver Damaged by Irradiation
Wang, S., Hyun, J., Youn, B., & Jung, Y. (2012) · Radiation Research · doi:10.1667/rr3091.1 · Cited by 34 · see citing works
Rangwala, F. A., Williams, K. P., Smith, G. R., Thomas, Z., Allensworth, J. L., Lyerly, H. K., Diehl, A. M., Morse, M. A., & Devi, G. R. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-402 · Cited by 33 · see citing works
Self-citationChen, T., Dalton, G. D., Oh, S., Maeso‐Díaz, R., Du, K., Meyers, R. A., Guy, C. D., Abdelmalek, M. F., Henao, R., Guarnieri, P., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.12.008 · Cited by 31 · see citing works
Self-citationPathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets
Santos-Laso, A., Gutiérrez-Larrañaga, M., Alonso-Peña, M., Medina, J. M., Iruzubieta, P., Arias-Loste, M., López-Hoyos, M., & Crespo, J. (2021) · Biomedicines · doi:10.3390/biomedicines10010046 · Cited by 31 · see citing works
Chan, A. W. H., Yu, S., Yu, Y., TONG, J. H. M., Wang, L., Tin, E. K. Y., Chong, C. C. N., Chan, S. L., Wong, G. L., Wong, V. W., et al. (2016) · Histopathology · doi:10.1111/his.13029 · Cited by 31 · see citing works
Maeso‐Díaz, R., Du, K., Pan, C. C., Guy, C. D., Oh, S., Chen, T., Wang, L., Ko, D. C., Tang, L., Dutta, R. K., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000401 · Cited by 30 · see citing works
Self-citationPotential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse
Hyun, J., Choi, S. S., Diehl, A. M., & Jung, Y. (2013) · Journal of Molecular Histology · doi:10.1007/s10735-013-9532-5 · Cited by 30 · see citing works
Self-citationMechanisms of liver fibrosis in metabolic syndrome
Mehal, W. (2023) · eGastroenterology · doi:10.1136/egastro-2023-100015 · Cited by 28 · see citing works
Oniciu, D. C., Hashiguchi, T., Shibazaki, Y., & Bisgaier, C. L. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194568 · Cited by 27 · see citing works
Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)
Subramanian, P., Hampe, J., Tacke, F., & Chavakis, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23136996 · Cited by 32 · see citing works
Structure, Function, and Responses to Injury
Crawford, J. M., Bioulac‐Sage, P., & Hytiroglou, P. (2017) · Elsevier eBooks · doi:10.1016/b978-0-7020-6697-9.00001-7 · Cited by 27 · see citing works
Hemodynamic changes in hepatic sinusoids of hepatic steatosis mice
Fan, J., Chen, C.-J., Wang, Y.-C., Quan, W., Wang, J., & Zhang, W. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i11.1355 · Cited by 27 · see citing works
Yu, Q., & Song, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1431652 · Cited by 27 · see citing works
- Authors
- Rangwala, F., Guy, C. D., Lu, J., Suzuki, A., Burchette, J. L., Abdelmalek, M. F., Chen, W., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- Corresponding author
- Diehl, Anna Mae
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2011-05-05
- Volume
- 224
- Issue
- 3
- Pages
- 401-410
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- PMC
- PMC3628812
- OpenAlex
- W2021688906
- Cited by
- 201
- References
- 35
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 16 · 2023: 18 · 2022: 16 · 2021: 13 · 2020: 13 · 2019: 15 · 2018: 17 · 2017: 12 · 2016: 13 · 2015: 11 · 2014: 11 · 2013: 8 · 2012: 10
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- The National Institute of Health (RO1 DK077794, RO1 AA010154)
- Duke Oncology Training (T32 302-0202)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Sonic hedgehog, nonalcoholic steatohepatitis, endoplasmic reticulum stress, liver fibrosis, Hedgehog signaling, paracrine signaling, stromal cells, myofibroblasts, tunicamycin, cyclopamine, GLI2, hepatocyte ballooning
- MeSH terms
- Zinc Finger Protein Gli2, Adult, Animals, Biopsy, Cells, Cultured, Endoplasmic Reticulum, Fatty Liver, Humans, Keratins, Ligands, Liver, Mice, Inbred C57BL, Middle Aged, Nuclear Proteins, Stress, Physiological, Tunicamycin, Stromal Cells, alpha 1-Antitrypsin Deficiency, Hepatocytes, Proto-Oncogene Proteins c-akt, Mice, Kruppel-Like Transcription Factors, Hedgehog Proteins, Myofibroblasts
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
