NKT-Associated Hedgehog and Osteopontin Drive Fibrogenesis in Non-Alcoholic Fatty Liver Disease
Open accessAbstract
Objective: Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. Design: The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. Results: When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18‒/‒ and CD1d‒/‒ mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. Conclusion: Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis.
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?
NKT conditioned medium stimulates HSC activation in culture, suggesting a direct fibrogenic role for NKT paracrine signaling.
“Moreover, NKT conditioned medium stimulates HSC activation in culture, suggesting a direct fibrogenic role for NKT paracrine signaling (118).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [118]
NKT cells secrete HSC activating ligands sonic hedgehog (Shh) and osteopontin (Opn) in the MCD mouse model of NASH.
“NKT cells secrete HSC activating ligands sonic hedgehog (Shh) and osteopontin (Opn) in the MCD mouse model of NASH (117–120).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [118]
NKT cells are much more abundant in mouse livers than in humans, and they promote NASH, fibrosis, and carcinogenesis in experimental models.
“NKT cells are much more abundant in mouse livers than in humans, and they promote NASH, fibrosis and carcinogenesis in experimental models.86,96,97”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [96]
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
The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study
Adams, L. A., Lymp, J. F., St. Sauver, J., Sanderson, S. O., Lindor, K. D., Feldstein, A., & Angulo, P. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.04.014 · Cited by 2,890 · see citing works
Bendelac, A. S., Savage, P. B., & Teyton, L. (2006) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141711 · Cited by 2,169 · see citing works
TOWARD AN UNDERSTANDING OF NKT CELL BIOLOGY: Progress and Paradoxes
Kronenberg, M. (2005) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115742 · Cited by 1,030 · see citing works
Liver: An organ with predominant innate immunity
Gao, B., Jeong, W.-I., & Tian, Z. (2008) · Hepatology · doi:10.1002/hep.22034 · Cited by 952 · see citing works
Intravascular Immune Surveillance by CXCR6+ NKT Cells Patrolling Liver Sinusoids
Geissmann, F., Cameron, T. O., Sidobre, S., Manlongat, N., Kronenberg, M., Briskin, M., Dustin, M. L., & Littman, D. R. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030113 · Cited by 681 · see citing works
Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases
Gao, B., Radaeva, S., & Park, O. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0309135 · Cited by 380 · see citing works
Dietary Factors Alter Hepatic Innate Immune System in Mice With Nonalcoholic Ratty Liver Disease * #
Li, Z., Soloski, M. J., & Diehl, A. M. (2005) · Hepatology · doi:10.1002/hep.20826 · Cited by 294 · see citing works
Self-citationAccumulation of natural killer T cells in progressive nonalcoholic fatty liver disease
Syn, W.-K., Oo, Y. H., Pereira, T. A., Karaca, G. F., Jung, Y., Omenetti, A., Witek, R. P., Choi, S. S., Guy, C. D., Fearing, C. M., et al. (2010) · Hepatology · doi:10.1002/hep.23599 · Cited by 283 · 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-citationSyn, 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-citationOsteopontin as a mediator of NKT cell function in T cell-mediated liver diseases.
Diao, H., Kon, S., Iwabuchi, K., Kimura, C., Morimoto, J., Ito, D., Segawa, T., Maeda, M., Hamuro, J., Nakayama, T., et al. (2004) · Immunity · doi:10.1016/j.immuni.2004.08.012 · Cited by 226 · 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-citationKita, H., Naidenko, O. V., Kronenberg, M., Ansari, A. A., Rogers, P., He, X.-S., Koning, F., Mikayama, T., de Water, J. V., Coppel, R. L., et al. (2002) · Gastroenterology · doi:10.1053/gast.2002.36020 · Cited by 218 · see citing works
Guebre‐Xabier, M., Yang, S., Lin, H. Z., Schwenk, R., Krzych, U., & Diehl, A. M. (2000) · Hepatology · doi:10.1002/hep.510310313 · Cited by 192 · see citing works
Self-citationPark, O., Jeong, W.-I., Wang, L., Wang, H., Lian, Z.-X., Gershwin, E. M., & Gao, B. (2009) · Hepatology · doi:10.1002/hep.22813 · Cited by 189 · 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-citationRNA Aptamer Blockade of Osteopontin Inhibits Growth and Metastasis of MDA-MB231 Breast Cancer Cells
Mi, Z., Guo, H., Russell, M. B., Liu, Y., Sullenger, B. A., & Kuo, P. C. (2008) · Molecular Therapy · doi:10.1038/mt.2008.235 · Cited by 157 · see citing works
Self-citationMethods for detection, isolation and culture of mouse and human invariant NKT cells
Watarai, H., Nakagawa, R., Omori‐Miyake, M., Dashtsoodol, N., & Taniguchi, M. (2007) · Nature Protocols · doi:10.1038/nprot.2007.515 · Cited by 140 · see citing works
NK and NKT cells in liver injury and fibrosis
Notas, G., Kisseleva, T., & Brenner, D. A. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.08.008 · Cited by 136 · see citing works
Tajiri, K., Shimizu, Y., Tsuneyama, K., & Sugiyama, T. (2009) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0b013e32831bc3d6 · Cited by 122 · see citing works
Stewart, G. A., Lowrey, J. A., Wakelin, S. J., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5451 · Cited by 108 · see citing works
Li, Z., Lin, H., Yang, S., et al. (2002) · Gastroenterology · doi:10.1053/gast.2002.35997 · Cited by 106 · see citing works
Jin, Z., Sun, R., Wei, H., Gao, X., Chen, Y., & Tian, Z. (2010) · Hepatology · doi:10.1002/hep.23983 · Cited by 100 · see citing works
Self-citationRepair‐related activation of hedgehog signaling promotes cholangiocyte chemokine production†
Omenetti, A., Syn, W., Jung, Y., Francis, H., Porrello, A., Witek, R. P., Choi, S. S., Yang, L., Mayo, M. J., Gershwin, M. E., et al. (2009) · Hepatology · doi:10.1002/hep.23019 · Cited by 100 · see citing works
Self-citationHepatic NKT cells: friend or foe?
Swain, M. G. (2008) · Clinical Science · doi:10.1042/cs20070328 · Cited by 80 · see citing works
Mallevaey, T., Fontaine, J., Breuilh, L., et al. (2007) · Infection and Immunity · doi:10.1128/iai.01178-06 · Cited by 75 · see citing works
Elevated plasma osteopontin level is predictive of cirrhosis in patients with hepatitis B infection
Zhao, L., Li, T., Wang, Y., Pan, Y.-L., Ning, H., Hui, X., Xie, H.-H., Wang, J., Han, Y., Liu, Z.-G., et al. (2007) · International journal of clinical practice · doi:10.1111/j.1742-1241.2007.01368.x · Cited by 74 · see citing works
Asanuma, T., Ono, M., Kubota, K., Hirose, A., Hayashi, Y., Saibara, T., Inanami, O., Ogawa, Y., Enzan, H., Onishi, S., et al. (2009) · Gut · doi:10.1136/gut.2009.176651 · Cited by 72 · see citing works
Role for hedgehog pathway in regulating growth and function of invariant NKT cells
Syn, W., Witek, R. P., Curbishley, S. M., Jung, Y., Choi, S. S., Enrich, B., Omenetti, A., Agboola, K. M., Fearing, C. M., Tilg, H., et al. (2009) · European Journal of Immunology · doi:10.1002/eji.200838890 · Cited by 58 · see citing works
Self-citationIntrahepatic natural killer T cell populations are increased in human hepatic steatosis
Adler, M. (2011) · World Journal of Gastroenterology · doi:10.3748/wjg.v17.i13.1725 · Cited by 57 · see citing works
CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice
Ishikawa, S., Ikejima, K., Yamagata, H., Aoyama, T., Kon, K., Arai, K., Takeda, K., & Watanabe, S. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.08.022 · Cited by 56 · see citing works
Similarities and Differences in the Pathogenesis of Alcoholic and Nonalcoholic Steatohepatitis
Syn, W., Teaberry, V. S., Choi, S. S., & Diehl, A. M. (2009) · Seminars in Liver Disease · doi:10.1055/s-0029-1214375 · Cited by 56 · see citing works
Self-citationHarada, K., Isse, K., Tsuneyama, K., Ohta, H., & Nakanuma, Y. (2003) · Liver International · doi:10.1034/j.1600-0676.2003.00807.x · Cited by 49 · see citing works
Huang, W., Zhu, G., Huang, M., Lou, G., Liu, Y., & Wang, S. (2010) · Clinica Chimica Acta · doi:10.1016/j.cca.2010.01.029 · Cited by 49 · see citing works
Sieghart, W., Wang, X., Schmid, K., Pinter, M., König, F., Bodingbauer, M., Wrba, F., Rasoul‐Rockenschaub, S., & Peck‐Radosavljevic, M. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.06.030 · Cited by 43 · see citing works
Lin, F., Li, Y., Cao, J., et al. (2010) · Molecular Biology Reports · doi:10.1007/s11033-010-0671-4 · Cited by 38 · see citing works
Croudace, J. E., Curbishley, S. M., Mura, M., et al. (2008) · BMC Immunology · doi:10.1186/1471-2172-9-71 · Cited by 21 · see citing works
Short peptides sensitize target cells to CTL specific for the MHC class Ib molecule, H2-M3
Dabhi, V. M., & Fischer Lindahl, K. (1998) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199811)28:11
Flagged first, then by citations
Cited by
Sorted by citations
The immunology of hepatocellular carcinoma
Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E., & Heikenwalder, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0044-z · Cited by 1,076 · 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
Immune cell-mediated features of non-alcoholic steatohepatitis
Huby, T., & Gautier, E. L. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00639-3 · Cited by 573 · see citing works
Adaptive immunity: an emerging player in the progression of NAFLD
Sutti, S., & Albano, E. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0210-2 · Cited by 374 · see citing works
An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH
Tacke, F., Puengel, T., Loomba, R., & Friedman, S. L. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.03.038 · Cited by 321 · see citing works
Horst, A. K., Neumann, K., Diehl, L., & Tiegs, G. (2016) · Cellular & Molecular Immunology · doi:10.1038/cmi.2015.112 · Cited by 295 · 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
Wehr, A., Baeck, C., Heymann, F., Niemietz, P. M., Hammerich, L., Martin, C., Zimmermann, H. W., Pack, O., Gassler, N., Hittatiya, K., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202909 · Cited by 268 · see citing works
The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity
Van Herck, M. A., Weyler, J., Kwanten, W. J., Dirinck, E. L., De Winter, B. Y., Francque, S. M., & Vonghia, L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00082 · Cited by 238 · see citing works
Pathophysiology of NASH: perspectives for a targeted treatment
Marra, F., & Lotersztajn, S. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990344 · Cited by 163 · see citing works
Machado, M. V., Michelotti, G. A., Pereira, T. A., Xie, G., Premont, R., Cortez-Pinto, H., & Diehl, A. M. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.05.031 · Cited by 135 · see citing works
Self-citationThe Emerging Role of B Cells in the Pathogenesis of NAFLD
Barrow, F., Khan, S., Wang, H., & Revelo, X. S. (2021) · Hepatology · doi:10.1002/hep.31889 · Cited by 126 · see citing works
Luo, X.-Y., Takahara, T., Kawai, K., Fujino, M., Sugiyama, T., Tsuneyama, K., Tsukada, K., Nakae, S., Zhong, L., & Li, X.-K. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00193.2013 · Cited by 120 · see citing works
Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy
Swiderska-Syn, M., Syn, W. K., Xie, G., Krüger, L., Machado, M. V., Karaca, G., Michelotti, G. A., Choi, S. S., Premont, R. T., & Diehl, A. M. (2014) · Gut · doi:10.1136/gutjnl-2013-305962 · Cited by 115 · see citing works
Self-citationSchulien, I., Hockenjos, B., Schmitt-Graeff, A., Perdekamp, M. G., Follo, M., Thimme, R., & Hasselblatt, P. (2019) · Cell Death & Differentiation · doi:10.1038/s41418-018-0239-8 · Cited by 111 · see citing works
Maricic, I., Marrero, I., Eguchi, A., Nakamura, R., Johnson, C. D., Dasgupta, S., Hernandez, C. D., Nguyen, P. S., Swafford, A. D., Knight, R., et al. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800614 · Cited by 92 · see citing works
Hepatic Stellate Cell-Immune Interactions in NASH
Carter, J. K., & Friedman, S. L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.867940 · Cited by 79 · 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
The immune landscape in nonalcoholic steatohepatitis
Narayanan, S., Surette, F. A., & Hahn, Y. S. (2016) · Immune Network · doi:10.4110/in.2016.16.3.147 · Cited by 64 · see citing works
Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions
Myint, M., Oppedisano, F., De Giorgi, V., Kim, B.-M., Marincola, F. M., Alter, H. J., & Nesci, S. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04627-0 · Cited by 61 · see citing works
The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC
Wu, Q., Yang, Y., Lin, S., Geller, D. A., & Yan, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1569915 · Cited by 32 · see citing works
Feng, D. (2020) · Liver Research · doi:10.1016/j.livres.2020.02.003 · Cited by 18 · see citing works
Pathophysiology of hepatic Na+/H+ exchange (Review)
Li, T., & Tuo, B. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8888 · Cited by 17 · see citing works
- Authors
- Syn, W.-K., Agboola, K. M., Swiderska, M., Michelotti, G. A., Liaskou, E., Pang, H., Xie, G., Philips, G., Chan, I. S., Karaca, G. F., Pereira, T. D. A., Chen, Y., Mi, Z., Kuo, P. C., Choi, S. S., Guy, C. D., Abdelmalek, M. F., & Diehl, A. M.
- Affiliations
- Duke University (US)
- University of Birmingham (GB)
- 1Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
- Loyola University Chicago (US)
- Duke Medical Center (US)
- Corresponding author
- Diehl, Anna Mae
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2012-03-17
- Volume
- 61
- Issue
- 9
- Pages
- 1323-1329
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC3578424
- OpenAlex
- W2106322659
- Cited by
- 266
- References
- 38
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 14 · 2023: 27 · 2022: 22 · 2021: 19 · 2020: 19 · 2019: 13 · 2018: 25 · 2017: 10 · 2016: 18 · 2015: 23 · 2014: 21 · 2013: 24 · 2012: 10
- FWCI
- 18.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Johns Hopkins University
- European Association for the Study of the Liver
- National Institutes of Health (RO1 DK053792)
- RIKEN
- National Cancer Institute (T32CA071341)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077794, R01DK053792)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, liver fibrosis, NKT cells, Hedgehog signaling, osteopontin, hepatic stellate cell activation, myofibroblast differentiation, CD1d, methionine-choline-deficient diet, plasma biomarkers, collagen gene expression
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Fatty Liver, Fibrosis, Humans, Immunohistochemistry, Liver, Lymphocyte Activation, Signal Transduction, Disease Progression, Mice, Osteopontin, Hedgehog Proteins, Hepatic Stellate Cells, Natural Killer T-Cells, Non-alcoholic Fatty Liver Disease
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
