Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease
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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 correlate with fibrosis in MASH patients, or MASH-associated hepatocytes in which increased cholesterol activates TAZ to drive Indian hedgehog expression and secretion.
“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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- 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 › Epidemiology › 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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