Yes-associated protein in kupffer cells enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis
Open accessAbstract
Background and Aims: Yes‐associated protein (YAP) plays an important role in hepatocarcinogenesis, although the potential role of YAP in non‐neoplastic liver diseases remains largely unknown. We report herein that YAP in Kupffer cells (KCs) enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis (NASH). Our data show that the expression of YAP is significantly increased in KCs of wild‐type mice fed a high‐fat diet (HFD). Approach and Results: We generated mice with macrophage/monocyte‐specific deletion of YAP (YAP ϕKO) or Toll‐like receptor 4 (TLR4; TLR4 ϕKO), and animals were fed an HFD or treated with lipopolysaccharide (LPS). Our data showed that YAP ϕKO mice fed an HFD exhibited lower serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels and less hepatic inflammation when compared to their littermate controls. LPS treatment induced accumulation of YAP in KCs in vitro and in mice, which was prevented by macrophage/monocyte‐specific deletion of TLR4 (TLR4 ϕKO). LPS transcriptionally activates YAP through activator protein 1 in macrophages/KCs. LPS‐induced YAP further enhances expression of proinflammatory cytokines (including monocyte chemoattractant protein 1, tumor necrosis factor alpha, and interleukin 6) through YAP association with the TEA domain–binding motif in the promoter region of inflammatory cytokines. Forced overexpression of active YAP (YAP5SA) in KCs enhanced the production of proinflammatory cytokines. Treatment of HFD‐fed mice with verteporfin inhibited KC activation, reduced liver inflammation, and decreased serum ALT/AST levels. Analyses of liver tissues from NASH patients reveal that YAP is increased in KCs and that level of YAP in human liver tissues is positively correlated with expression of proinflammatory cytokines. Conclusions: This study describes an important role of YAP in KCs for regulation of liver inflammation in NASH. Our findings suggest that inhibition of YAP may represent an effective therapeutic strategy for NASH treatment.
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NLRP3 activation in KCs promotes IL-1β, a critical pro-inflammatory cytokine which induces several components of the acute phase response.
“Concurrently, NLRP3 activation in KCs promotes IL-1β, a critical pro-inflammatory cytokine which induces several components of the acute phase response.[64], [65], [66]”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [66]
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- Authors
- Song, K., Kwon, H., Han, C., Chen, W., Zhang, J., Ma, W., Dash, S., Gandhi, C. R., & Wu, T.
- Affiliations
- Tulane University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Wu, Tong
- Venue
- Hepatology
- Published
- 2020-04-11
- Volume
- 72
- Issue
- 1
- Pages
- 72-87
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC7153981
- OpenAlex
- W2980915366
- Cited by
- 110
- References
- 38
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 18 · 2023: 20 · 2022: 19 · 2021: 13 · 2020: 8
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA102325, R01CA226281, R01CA219541)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- YAP, Kupffer cells, nonalcoholic steatohepatitis, inflammatory cytokines, liver inflammation, TLR4, lipopolysaccharide, high-fat diet, activator protein-1, MCP-1, TNF-α, interleukin-6, verteporfin, hepatocarcinogenesis
- MeSH terms
- YAP-Signaling Proteins, Alanine Transaminase, Animals, Aspartate Aminotransferases, Kupffer Cells, Male, Mice, Inbred C57BL, Transcription Factors, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, Mice
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