Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity
Open accessAbstract
Hedgehog (Hh) ligand production by ballooned hepatocytes drives nonalcoholic steatohepatitis (NASH) progression in mice. The NIDDK‐sponsored PIVENS trial (NCT00063622) showed that vitamin E (VitE) improved NASH. We investigated whether VitE treatment and improvement in NASH were associated with changes in Hh pathway activity. Immunohistochemistry (IHC) was performed on both pre‐ and posttreatment liver biopsies of 59 PIVENS patients randomized to VitE (n = 30) or placebo (n = 29). Sonic Hh (Shh) ligand‐producing cells and Shh‐responsive cells were quantified. The latter was accomplished by triple IHC for gli2+ (marker of Hh signaling), sox‐9 (progenitor marker), and α‐smooth muscle actin (α‐SMA; myofibroblast marker). Ballooned hepatocytes were quantified by keratin 8/18 and ubiquitin (K8/18/Ub) staining. IHC results were correlated with primary clinical and histologic PIVENS data. Pretreatment clinical, histologic, and IHC parameters did not differ significantly in the two treatment groups. Regardless of treatment arm, the number of Shh+ hepatocytes correlated with K8/18/Ub foci (r 2 = 0.47, P < 0.001) and aspartate aminotransferase (AST) (r 2 = 0.15, P = 0.002). Treatment‐related changes in the numbers of Shh+ hepatocytes correlated with changes in serum AST (partial r 2 = 0.75, P < 0.0001), hepatocyte ballooning ( P = 0.004), the ductular reaction (i.e., numbers of gli2+/sox9+ cells; P = 0.03 and α‐SMA+ cells; P = 0.10), and fibrosis stage ( P = 0.02). Treatment response was associated with a greater decrease in Shh+ hepatocytes than nonresponse ( P = 0.007). The VitE group demonstrated a greater reduction in K8/18/Ub+ foci ( P < 0.08) and Shh+ hepatocytes ( P < 0.05) than the placebo group, effects that became more significant after correction for baseline differences and multiple linear regression analysis. Conclusion : During PIVENS, treatment response correlated with loss of Shh+ hepatocytes and improvement in Hh‐regulated processes that promote NASH progression. (H epatology 2015;61:98–107)
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Hedgehog ligands via their receptor Patched promote activation of HSCs in vitro and in mice, and show a positive correlation with progression from steatosis to steatohepatitis and myofibroblast activation in human livers.
“In addition to regulating liver regeneration, hedgehog ligands, via their receptor Patched, promote the activation of HSCs in vitro and in mice, and show a positive correlation with progression from steatosis to steatohepatitis and myofibroblast activation in human livers.39,40”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [40]
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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: 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
Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Sanyal, A. J., Chalasani, N., Kowdley, K. V., McCullough, A., Diehl, A. M., Bass, N. M., Neuschwander-Tetri, B. A., Lavine, J. E., Tonascia, J., Unalp, A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907929 · Cited by 3,327 · see citing works
Self-citationThe mechanisms of Hedgehog signalling and its roles in development and disease
Briscoe, J., & Thérond, P. P. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3598 · Cited by 1,751 · see citing works
Loomba, R. S., & Sanyal, A. J. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.171 · Cited by 1,696 · see citing works
Brunt, E. M., Kleiner, D. E., Wilson, L. A., Belt, P., & Neuschwander-Tetri, B. A. (2011) · Hepatology · doi:10.1002/hep.24127 · Cited by 1,251 · see citing works
Ryoo, H. D., Gorenc, T., & Steller, H. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.08.019 · Cited by 624 · see citing works
Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox
Rubartelli, A., & Lotze, M. T. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.08.004 · Cited by 614 · see citing works
Richardson, M. M., Jonsson, J. R., Powell, E. E., Brunt, E. M., Neuschwander–Tetri, B. A., Bhathal, P. S., Dixon, J. B., Weltman, M. D., Tilg, H., Moschen, A. R., et al. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.05.012 · Cited by 482 · see citing works
Roskams, T., Yang, S. Q., Koteish, A., Durnez, A., DeVos, R., Huang, X., Achten, R., Verslype, C., & Diehl, A. M. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63489-x · Cited by 447 · see citing works
Self-citationLipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal
Alkhouri, N., Dixon, L. J., & Feldstein, A. E. (2009) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.09.32 · Cited by 400 · see citing works
Pospisilik, J. A., Schramek, D., Schnidar, H., Cronin, S. J. F., Nehme, N. T., Zhang, X., Knauf, C., Cani, P. D., Aumayr, K., Todoric, J., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.027 · Cited by 369 · see citing works
Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.11.017 · Cited by 346 · see citing works
Moylan, C. A., Pang, H., Dellinger, A. E., Suzuki, A., Garrett, M. E., Guy, C. D., Murphy, S. K., Ashley‐Koch, A. E., Choi, S. S., Michelotti, G. A., et al. (2013) · Hepatology · doi:10.1002/hep.26661 · Cited by 316 · see citing works
Self-citationHedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat
Teperino, R., Amann, S., Bayer, M., McGee, S. L., Loipetzberger, A., Connor, T., Jaeger, C., Kammerer, B., Winter, L., Wiche, G., et al. (2012) · Cell · doi:10.1016/j.cell.2012.09.021 · Cited by 284 · see citing works
Hedgehog Controls Hepatic Stellate Cell Fate by Regulating Metabolism
Chen, Y., Choi, S. S., Michelotti, G., Chan, I. S., Swiderska-Syn, M., Karaca, G., Xie, G., Moylan, C. A., Garibaldi, F., Premont, R., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.07.115 · Cited by 279 · see citing works
Self-citationHedgehog 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-citationSyn, W.-K., Choi, S. S., Liaskou, E., Karaca, G. F., Agboola, K. M., Oo, Y. H., Mi, Z., Pereira, T. A., Zdanowicz, M., Malladi, P., et al. (2011) · Hepatology · doi:10.1002/hep.23998 · Cited by 275 · see citing works
Self-citationWallace, K., Burt, A. D., & Wright, M. C. (2008) · Biochemical Journal · doi:10.1042/bj20071570 · Cited by 273 · see citing works
Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH
Sutti, S., Jindal, A., Locatelli, I., Vacchiano, M., Gigliotti, L., Bozzola, C., & Albano, E. (2014) · Hepatology · doi:10.1002/hep.26749 · Cited by 270 · see citing works
Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches
Schuppan, D., & Schattenberg, J. M. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12212 · Cited by 256 · see citing works
Hepatocellular 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
Fan, Y., & Bergmann, A. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.01.003 · Cited by 238 · 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-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-citationIncreased production of sonic hedgehog by ballooned hepatocytes
Rangwala, F., Guy, C. D., Lu, J., Suzuki, A., Burchette, J. L., Abdelmalek, M. F., Chen, W., & Diehl, A. M. (2011) · The Journal of Pathology · doi:10.1002/path.2888 · Cited by 201 · see citing works
Self-citationTickle, C. A., & Eichele, G. (1994) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.10.110194.001005 · Cited by 201 · see citing works
Cell-to-Cell Heterogeneity in Lipid Droplets Suggests a Mechanism to Reduce Lipotoxicity
Herms, A., Bosch, M., Ariotti, N., Reddy, B. J. N., Fajardo, A., Fernández‐Vidal, A., Álvarez-Guaita, A., Fernandez-Rojo, M. A., Rentero, C., Tebar, F., et al. (2013) · Current Biology · doi:10.1016/j.cub.2013.06.032 · Cited by 193 · see citing works
Pediatric nonalcoholic fatty liver disease (NAFLD): A “growing” problem?
Roberts, E. A. (2007) · Journal of Hepatology · doi:10.1016/j.jhep.2007.03.003 · Cited by 180 · see citing works
Pajvani, U. B., Qiang, L., Kangsamaksin, T., Kitajewski, J., Ginsberg, H. N., & Accili, D. (2013) · Nature Medicine · doi:10.1038/nm.3259 · Cited by 168 · see citing works
Signals 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-citationFactor, V. M., Laskowska, D., Jensen, M. R., Woitach, J. T., Popescu, N. C., & Thorgeirsson, S. S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.040428797 · Cited by 148 · see citing works
Pathologic 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
Apoptosis in Drosophila: compensatory proliferation and undead cells
Martín, F. A., Pérez-Garijo, A., & Morata, G. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.072447fm · Cited by 139 · see citing works
The role of Hedgehog signaling in fibrogenic liver repair
Choi, S. S., Omenetti, A., Syn, W., & Diehl, A. M. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.10.015 · Cited by 117 · see citing works
Self-citationOmenetti, 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-citationMitogenic signaling from apoptotic cells in Drosophila
Morata, G., Shlevkov, E., & Pérez-Garijo, A. (2011) · Development Growth & Differentiation · doi:10.1111/j.1440-169x.2010.01225.x · Cited by 101 · see citing works
Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development
McGlinn, E., van Bueren, K. L., Fiorenza, S., Mo, R., Poh, A. M., Forrest, A. R. R., Soares, M. B., Bonaldo, M. F., Grimmond, S. M., Hui, C., et al. (2005) · Mechanisms of Development · doi:10.1016/j.mod.2005.06.012 · Cited by 97 · 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
Thakur, P. C., Stuckenholz, C., Rivera, M. R., et al. (2011) · Hepatology · doi:10.1002/hep.24349 · Cited by 86 · see citing works
Targeting hedgehog signaling in cancer: research and clinical developments
Xie, J., Bartels, C. M., Gu, D., & Barton, S. W. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s34678 · Cited by 66 · 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
Ge, X., Leung, T., Arriazu, E., Lu, Y., Urtasun, R., Christensen, B., Fiel, M. I., Mochida, S., Sφrensen, E. S., & Nieto, N. (2013) · Hepatology · doi:10.1002/hep.26931 · 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-citationParacrine 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-citationIaffaldano, P., Ruggieri, M., Viterbo, R., Mastrapasqua, M., & Trojano, M. (2014) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2013.08.009 · Cited by 44 · see citing works
Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling
Wang, J., Mook, R. A., Lü, J., Gooden, D. M., Ribeiro, A. A., Guo, A., Barak, L. S., Lyerly, H. K., & Chen, W. (2012) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2012.09.030 · Cited by 30 · see citing works
Hung, P. S.-P., Sheu, M., Chieh, M., Hu, J., Sun, Y., Lee, C.-C., Chung, Y., Tsai, Y., Wang, J., & Chen, C.-L. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.09.003 · Cited by 21 · see citing works
Miyazaki, M., Bai, L., Tsuboi, S., et al. (1991) · PubMed · doi:10.18926/amo/32182 · Cited by 9 · see citing works
The acrolein cytotoxicity and cytoprotective action of α-tocopherol
Watanabe, M., Sugimoto, M., & Ito, K. (1992) · Gastroenterologia Japonica · doi:10.1007/bf02777723 · Cited by 7 · see citing works
Hishinuma, I., & Nakamura, T. (1988) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.34.11 · Cited by 6 · see citing works
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- Authors
- Guy, C. D., Suzuki, A., Abdelmalek, M. F., Burchette, J. L., Diehl, A. M., & CRN, F. T. N.
- Affiliations
- Duke Medical Center (US)
- Division of Gastroenterology & Hepatology,University of Arkansas,Little Rock,AR
- Duke University (US)
- Corresponding author
- Diehl, Anna Mae
- Venue
- Hepatology
- Published
- 2014-08-25
- Volume
- 61
- Issue
- 1
- Pages
- 98-107
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4241186
- OpenAlex
- W2163837559
- Cited by
- 72
- References
- 52
- Citations by year
- 2026: 4 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 11 · 2017: 8 · 2016: 9 · 2015: 11 · 2014: 4
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UO1DK061713, R01DK053792, RC2AA019399, R01DK077794)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- nonalcoholic steatohepatitis, Hedgehog signaling, Sonic hedgehog, vitamin E, hepatocyte ballooning, treatment response, liver fibrosis, ductular reaction, myofibroblasts, liver biopsy histology, aspartate aminotransferase
- MeSH terms
- Adult, Alanine Transaminase, Aspartate Aminotransferases, Cross-Sectional Studies, Female, Fibrosis, Humans, Immunohistochemistry, Liver, Male, Middle Aged, Vitamin E, Vitamins, Treatment Outcome, Hepatocytes, Hedgehog Proteins, Non-alcoholic Fatty Liver Disease
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