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Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis
Open accessAbstract
Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc+/−) (overly active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine and choline–deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc+/− mice expressed more OPN and developed worse liver fibrosis ( P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis ( P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression ( P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs ( P < 0.05); neutralizing OPN with RNA aptamers attenuated this ( P < 0.05). Conclusion: OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH (Hepatology 2011)
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“Like hepatocytes, cholangiocytes can undergo lipoapoptosis and senescence in the presence of increased saturated fatty acids, which may provoke release of damage-associated molecular patterns, senescence-associated secretory patterns (such as chemokine ligand 2 (CCL2)), and SPP1, which activate HSCs to generate fibrosis (37-40).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [38]
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“SPP1, a downstream target of hedgehog signaling, is induced in myofibroblasts in MASH, and its antagonism reduces fibrosis in the MCD mouse model (38, 159).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [38]
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Cites
Nonalcoholic Steatohepatitis: A Proposal for Grading and Staging The Histological Lesions
Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A., & Bacon, B. R. (1999) · American Journal of Gastroenterology · doi:10.1111/j.1572-0241.1999.01377.x · Cited by 3,907
Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity
Ashkar, S., Weber, G. F., Panoutsakopoulou, V., Sanchirico, M. E., Jansson, M., Zawaideh, S., Rittling, S. R., Denhardt, D. T., Glimcher, M. J., & Cantor, H. (2000) · Science · doi:10.1126/science.287.5454.860 · Cited by 1,125
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
The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease
Chabas, D., Baranzini, S. E., Mitchell, D., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M., Pedotti, R., et al. (2001) · Science · doi:10.1126/science.1062960 · Cited by 829
Osteopontin: role in cell signaling and cancer progression
Rangaswami, H., Bulbule, A., & Kundu, G. C. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.12.005 · Cited by 738
THE INFLUENCE OF THE PROINFLAMMATORY CYTOKINE, OSTEOPONTIN, ON AUTOIMMUNE DEMYELINATING DISEASE
Chabas, D., Baranzini, S. E., Mitchell, D. J., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M. V., Pedotti, R., et al. (2002) · International Conference on Osteopontin and SIBLING Proteins · doi:10.1100/tsw.2002.326 · Cited by 729
Wieckowska, A., Zein, N. N., Yerian, L. M., López, R., McCullough, A. J., & Feldstein, A. E. (2006) · Hepatology · doi:10.1002/hep.21223 · Cited by 675
Kupffer Cell Engulfment of Apoptotic Bodies Stimulates Death Ligand and Cytokine Expression
Canbay, A. E., Feldstein, A. E., Higuchi, H., Werneburg, N., Grambihler, A., Bronk, S. F., & Gores, G. J. (2003) · Hepatology · doi:10.1053/jhep.2003.50472 · Cited by 470
Omenetti, A., Porrello, A., Jung, Y., Yang, L., Popov, Y. V., Choi, S. S., Witek, R. P., Alpini, G. D., Venter, J., VanDongen, H. M. A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35875 · Cited by 346
Self-citationAnimal models of NASH: Getting both pathology and metabolic context right
Larter, C. Z., & Yeh, M. M. (2008) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2008.05543.x · Cited by 340
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Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., et al. (2019) · Nature · doi:10.1038/s41586-019-1631-3 · Cited by 1,784
Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
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Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis
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Metadata
- Authors
- Syn, 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., Chen, Y., Moylan, C., Jung, Y., Bhattacharya, S. D., Teaberry, V., Omenetti, A., Abdelmalek, M. F., Guy, C. D., Adams, D. H., Kuo, P. C., Michelotti, G. A., Whitington, P. F., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- University of Birmingham (GB)
- Northwestern University (US)
- Corresponding author
- Syn, Wing-Kin
- Diehl, Anna Mae
- ORCID
- Venue
- Hepatology
- Published
- 2011-01
- Volume
- 53
- Issue
- 1
- Pages
- 106-115
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3025083
- OpenAlex
- W2039567228
- Cited by
- 275
- References
- 40
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 18 · 2023: 18 · 2022: 19 · 2021: 19 · 2020: 13 · 2019: 14 · 2018: 18 · 2017: 16 · 2016: 17 · 2015: 23 · 2014: 25 · 2013: 15 · 2012: 23
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust
- Alberta Innovates - Health Solutions
- National Institutes of Health (1k08dk080980-01a1, 1r01aa014257-01a2)
- National Institute on Alcohol Abuse and Alcoholism (R01 AA014257, 5R01AA14257-5)
- National Institute of General Medical Sciences (R01GM065113)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077794, K08 DK-080980, R01DK053792)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- osteopontin, Hedgehog signaling, nonalcoholic steatohepatitis, liver fibrosis, hepatic stellate cells, Patched1, methionine-choline-deficient diet, cholangiocytes, extracellular matrix, fibrosis progression, RNA aptamers, cyclopamine, sag
- MeSH terms
- Animals, Cell Line, Choline Deficiency, Diet, Fatty Liver, Humans, Liver Cirrhosis, Methionine, Mice, Inbred C57BL, Veratrum Alkaloids, Up-Regulation, Mice, Osteopontin, Hedgehog Proteins, Hepatic Stellate Cells, Non-alcoholic Fatty Liver Disease
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