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Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease
Open accessAbstract
Background & aims Mechanisms that regulate regeneration of injured livers are complex. YAP, a stem cell associated factor, controls liver growth in healthy adult mice. Increasing nuclear localization of YAP triggers accumulation of reactive-appearing ductular cells (YAP+RDC) with liver progenitor capabilities. The significance of YAP activation, and mechanisms involved, are unknown in diseased livers. We evaluated the hypothesis that YAP is more activated in injured livers that are scarring than in those that are regenerating effectively.Methods Immunohistochemistry and qRT-PCR analysis were used to localize and quantify changes in YAP and RDC in 52 patients with non-alcoholic fatty liver disease (NAFLD) and two mouse models of diet-induced non-alcoholic steatohepatitis (NASH). Results were correlated with liver disease severity, metabolic risk factors, and factors proven to control NAFLD progression.Results YAP increased in NAFLD where it mainly localized in nuclei of RDC that expressed progenitor markers. Accumulation of YAP+RDC paralleled the severity of hepatocyte injury and accumulation of Sonic hedgehog, but not steatosis or metabolic risk factors. YAP+RDC expressed osteopontin, a Shh-regulated fibrogenic factor. Myofibroblast accumulation, fibrosis, and numbers of YAP+RDC strongly correlated. In murine NASH models, atrophic fibrotic livers contained significantly more YAP+RDC than livers with less severe NASH.Conclusion YAP+RDC promote scarring, rather than effective regeneration, during NASH.
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“Other major sources of hedgehog ligands may be reactive-appearing ductular cells that strongly correlate with fibrosis in patients with MASH or in MASH-associated hepatocytes where increased cholesterol intake activate TAZ to drive Indian hedgehog expression and secretion (112, 113, 163).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [163]
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“In NAFLD patient tissues and NASH mouse model, YAP was upregulated in the nuclei of reactive ductal cells (RDCs) responsible for production of pro-fibrogenic factors and expansion of YAP + RDCs cell population correlated with myofibro-blast accumulation and fibrosis [67].”
BackgroundAbe, M., Yoshida, T., Akiba, J., Ikezono, Y., Wada, F., Masuda, A., Sakaue, T., Tanaka, T., Iwamoto, H., Nakamura, T., et al. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i37.6833 · Cited by 18
Intricate role of yes‐associated protein1 in human liver cirrhosis: TGF‐β1 still is a giant player
Mohagheghi, S., Geramizadeh, B., Nikeghbalian, S., Khodadadi, I., Karimi, J., Khajehahmadi, Z., Gharekhanloo, F., & Tavilani, H. (2019) · IUBMB Life · doi:10.1002/iub.2052 · Cited by 18
“In a murine model of NASH, it has been shown that the levels of nuclear YAP1 are considerably correlated with fibrosis, TGF-β1 signaling, and the expression of the target genes of YAP1 such as CTGF.25 Also, the nuclear localization of YAP1 was reported in various types of adult and pediatric cholestatic liver diseases…”
BackgroundInfluentialLiver knockout YAP gene improved insulin resistance-induced hepatic fibrosis
Dai, Y., Peng, H. F., Sun, Z., Guo, Z., Xu, H., Xue, L., Song, H., Li, Y., Li, S., Gao, M., et al. (2021) · Journal of Endocrinology · doi:10.1530/joe-20-0561 · Cited by 17
Pathogenesis of Nonalcoholic Fatty Liver Disease
Machado, M. V., & Diehl, A. M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-37591-7.00025-2 · Cited by 17
Self-citationMyofibroblast YAP/TAZ is dispensable for liver fibrosis in mice
Xu, L., Wettschureck, N., Bai, Y., Yuan, Z., & Wang, S. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.02.026 · Cited by 17
Nyholm, I., Sjöblom, N., Pihlajoki, M., Hukkinen, M., Lohi, J., Heikkilä, P., Mutka, A., Jahnukainen, T., Davenport, M., Heikinheimo, M., et al. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000333 · Cited by 16
Li, L., Yang, C., Li, S., Liu, Y., Li, H.-D., Hu, S., Zhou, H., Wang, J., Shen, H., Meng, X., et al. (2020) · Inflammation Research · doi:10.1007/s00011-020-01360-y · Cited by 16
Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression
Lee, N. Y., Choi, M. G., Lee, E. J., & Koo, J. H. (2024) · Archives of Pharmacal Research · doi:10.1007/s12272-024-01501-5 · Cited by 17
“Moreover, the extent of YAP activity is frequently correlated with the severity of fibrosis (Machado et al. 2015; Salloum et al. 2021).”
BackgroundInfluentialShh‐Yap signaling controls hepatic ductular reactions in CCl4 ‐induced liver injury
Jin, L., Huang, H., Ni, J., Shen, J., Liu, Z., Li, L., Fu, S., Yan, J., & Hu, B. (2020) · Environmental Toxicology · doi:10.1002/tox.23025 · Cited by 14
“The accumulation of Yap-positive ductular reaction cells is also strongly correlated with the number of Shh-positive cells in patients with nonalcoholic fatty liver disease.(15) Our results also revealed that inhibition of Shh signaling by Gant61 reduced Shh and Yap1 activity, indicating that Yap1 is a downstream effe…”
BackgroundInfluentialMeng, L., Goto, M., Tanaka, H., Kamikokura, Y., Fujii, Y., Okada, Y., Furukawa, H., & Nishikawa, Y. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.06.001 · Cited by 15
Ichimura‐Shimizu, M., Tsuchiyama, Y., Morimoto, Y., Matsumoto, M., Kobayashi, T., Sumida, S., Kakimoto, T., Oya, T., Ogawa, H., Yamashita, M., et al. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.10.002 · Cited by 15
Zhao, W., Yuan, W., Dong, T., Qi, W., Feng, Z., Li, C., & Sun, Y. (2025) · Communications Biology · doi:10.1038/s42003-025-08160-2 · Cited by 16
Wehling, L., Keegan, L., Fernández‐Palanca, P., Hassan, R. A. R. A., Ghallab, A., Schmitt, J., Tang, Y., Marois, M. L., Roessler, S. K., Schirmacher, P., et al. (2022) · eLife · doi:10.7554/elife.78540 · Cited by 14
The Neglected Role of Bile Duct Epithelial Cells in NASH
Cadamuro, M., Lasagni, A., Sarcognato, S., Guido, M., Fabris, R., Strazzabosco, M., Strain, A. J., Simioni, P., Villa, E., & Fabris, L. (2021) · Seminars in Liver Disease · doi:10.1055/s-0041-1739455 · Cited by 13
Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals
Zhao, Y., Wang, H., He, T., Ma, B., Chen, G., & Tzeng, C. (2023) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-023-00775-6 · Cited by 13
“Myofibroblastic HSCs cause up-regulation of α-smooth muscle actin (α-SMA) and Desmin, and secretion of ECM such as types I collagen (Col1a1), thereby resulting in matrix deposition and scar formation (Wells and Schwabe 2015).”
BackgroundWang, W., He, Y., & Liu, Q. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12126 · Cited by 13
“Liver dysfunction is accompanied by an increase in the YAP expres‐ sion in MAFLD and HIPPO pathway activation can reduce liver damage (27,28).”
BackgroundJohnson, R. L. (2019) · Science China Life Sciences · doi:10.1007/s11427-018-9510-3 · Cited by 13
YAP as a potential therapeutic target for myofibroblast formation in asthma
Guo, Y., Zhou, Y., Wang, R., Lin, Y., Lan, H., Yang, L., Wang, D., Dong, J., Li, K., Yan, Y., et al. (2025) · Respiratory Research · doi:10.1186/s12931-025-03115-x · Cited by 13
“In the liver, YAP activity correlates with the accumulation of reactive ductal cells and myofibroblasts, which are essential in the progression of fibrosis in non-alcoholic steatohepatitis (NASH) [19].”
Ductular reaction in non-alcoholic fatty liver disease: When Macbeth is perverted
He, Y.-H., Pan, J., Xu, L., Gu, T., & Chen, Y. (2023) · World Journal of Hepatology · doi:10.4254/wjh.v15.i6.725 · Cited by 11
Hamesch, K., Güldiken, N., Aly, M., Hüser, N., Hartmann, D., Rufat, P., Ziol, M., Remih, K., Lurje, G., Scheiner, B., et al. (2020) · BMC Medicine · doi:10.1186/s12916-020-01784-7 · Cited by 11
A systems biology approach to study non-alcoholic fatty liver (NAFL) in women with obesity
Meijnikman, A. S., Lappa, D., Herrema, H., Aydin, Ö., Krautkramer, K. A., Tremaroli, V., Olofsson, L. E., Lundqvist, A., Bruin, S. C., Acherman, Y. I. Z., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104828 · Cited by 12
“Of interest, TRIP6, is an upstream activator of the transcriptional co-activators YAP (or YAP1) and TAZ and are involved in the pathogenesis of NAFLD (Machado et al., 2015; Wang et al., 2016).”
BackgroundShi, N., Sun, K., Tang, H., & Mao, J. (2023) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.24943 · Cited by 10
Chen, D., Zhang, H., Zhang, X., Sun, X., Qin, Q., Hou, Y., Jia, M., & Chen, Y. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113166 · Cited by 8
Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
Yıldız, E., Alam, G. E., Perino, A., Jalil, A., Denechaud, P., Huber, K., Fajas, L., Auwerx, J. H., Sorrentino, G., & Schoonjans, K. (2022) · eLife · doi:10.7554/elife.81926 · Cited by 10
“YAP has been found to be activated in BECs in fibrotic livers but not in steatosis (Machado et al., 2015), suggesting that YAP activation is necessary to support DR in the late fibrotic NAFLD stages, and thus, leaving the early molecular mechanisms of BEC activation, which precede the onset of the DR, unexplored.”
BackgroundKarachaliou, G. S., Suzuki, A., Patel, V. A., Bastian, L. A., Diehl, A. M., Abdelmalek, M. F., Moylan, C. A., Guy, C. D., & Wang, Y. (2023) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2023.05.027 · Cited by 8
Self-citationCD133‐Src‐TAZ signaling stimulates ductal fibrosis following DDC diet‐induced liver injury
Oh, H. T., Heo, W., Yoo, G. D., Kim, K. M., Hwang, J., Hwang, E. S., Ko, J., Ko, Y., & Hong, J. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30899 · Cited by 7
“YAP‐positive ductal cells accumulate with progression of fibrosis in human NASH (Machado et al., 2015).”
BackgroundExperimental models of hepatic fibrosis
Muriel, P. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-99764-5.00004-4 · Cited by 7
Regulation of Hippo-YAP1/TAZ pathway in metabolic dysfunction-associated steatotic liver disease
Xuan, W., Song, D., Hou, J., & Meng, X. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1505117 · Cited by 8
The immune duality of osteopontin and its therapeutic implications for kidney transplantation
Leung, J., Qu, L., Ye, Q., & Zhong, Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1520777 · Cited by 6
Li, Y., Dong, L., Yin, X., Wang, X., Zhu, X., Zheng, P., & Tang, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e31621 · Cited by 6
Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease
Cebola, I. (2020) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1480 · Cited by 5
“, 2018) and found YAP increased in multiple NAFLD models, in which expression and accumulation of YAP correlated with hepatocyte injury severity (P. Chen et al., 2018; Jeong et al., 2018; Kodama et al., 2018; Machado et al., 2015).”
BackgroundDevilish Effects of Taz in Nonalcoholic Steatohepatitis
Friedman, S. L., & Lee, Y. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.10.006 · Cited by 5
“More recently, however, both Yap and Taz have been identified as regulators of metabolism and nutrient-sensing (Santinon et al., 2016), but only a single report has ascribed to Yap a role in NASH (Machado et al., 2015).”
BackgroundEP300/YAP1-SERPINE1 Signaling Regulates Ductular Reaction and Liver Fibrosis in Biliary Atresia
Zhu, Z., Lu, C., Lv, X., Lü, Y., Zhu, W., Zhu, Y., Zhang, R., Ding, Z., Xie, H. Q., & Tang, W. (2025) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2025.101640 · Cited by 4
“23 In liver carcinogenesis, YAP1 interacts in a complex manner with transforming growth factor-ß (TGF-ß ), Wnt/ ß -Catenin, Notch, and the insulin-like growth factor (IGF) pathway.”
Du, J., Wang, G., Zhao, Y., Li, M., Yang, S., & Liu, L. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115886 · Cited by 4
Metadata
- Authors
- Machado, M. V., Michelotti, G. A., Pereira, T. A., Xie, G., Premont, R., Cortez-Pinto, H., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- Corresponding author
- Diehl, Anna Mae
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 63
- Issue
- 4
- Pages
- 962-970
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC4575842
- OpenAlex
- W2130148732
- Cited by
- 135
- References
- 43
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 7 · 2023: 11 · 2022: 21 · 2021: 19 · 2020: 14 · 2019: 13 · 2018: 8 · 2017: 7 · 2016: 11 · 2015: 1
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r37aa010154-20)
- National Institute on Alcohol Abuse and Alcoholism (R37 AA-010154)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK0077794, R01DK077794, DK053792, R01DK053792)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- YAP, liver fibrosis, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, liver regeneration, Sonic hedgehog, osteopontin, myofibroblasts, hepatocyte injury, liver progenitor cells
- MeSH terms
- YAP-Signaling Proteins, Adult, Animals, Bile Ducts, Intrahepatic, Biopsy, Female, Gene Expression Regulation, Humans, Immunohistochemistry, Liver Cirrhosis, Experimental, Male, Mice, Inbred C57BL, Phosphoproteins, RNA, Messenger, Blotting, Western, Disease Progression, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Adaptor Proteins, Signal Transducing, Mice, Non-alcoholic Fatty Liver Disease
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