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Cited by 162Liver physiology and pathologyHippo pathway signaling and YAP/TAZLiver Disease Diagnosis and Treatment

Hepatocyte Stress Increases Expression of Yes‐Associated Protein and Transcriptional Coactivator With PDZ‐Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis

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Mooring, Meghan, Fowl, Brendan H., Lum, Shelly Z.C., Liu, Ye, Yao, Kangning, Softic, Samir, Kirchner, Rory, Bernstein, Aaron +5 more·2020·Hepatology
DOI 10.1002/hep.30928PMC PMC7062580
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Abstract

Background and Aims: Activated hepatocytes are hypothesized to be a major source of signals that drive cirrhosis, but the biochemical pathways that convert hepatocytes into such a state are unclear. We examined the role of the Hippo pathway transcriptional coactivators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ) in hepatocytes to facilitate cell–cell interactions that stimulate liver inflammation and fibrosis. Approach and Results: Using a variety of genetic, metabolic, and liver injury models in mice, we manipulated Hippo signaling in hepatocytes and examined its effects in nonparenchymal cells to promote liver inflammation and fibrosis. YAP‐expressing hepatocytes rapidly and potently activate the expression of proteins that promote fibrosis (collagen type I alpha 1 chain, tissue inhibitor of metalloproteinase 1, platelet‐derived growth factor c, transforming growth factor β2) and inflammation (tumor necrosis factor, interleukin 1β). They stimulate expansion of myofibroblasts and immune cells, followed by aggressive liver fibrosis. In contrast, hepatocyte‐specific YAP and YAP/TAZ knockouts exhibit limited myofibroblast expansion, less inflammation, and decreased fibrosis after CCl 4 injury despite a similar degree of necrosis as controls. We identified cellular communication network factor 1 (CYR61) as a chemokine that is up‐regulated by hepatocytes during liver injury but is expressed at significantly lower levels in mice with hepatocyte‐specific deletion of YAP or TAZ. Gain‐of‐function and loss‐of‐function experiments with CYR61 in vivo point to it being a key chemokine controlling liver fibrosis and inflammation in the context of YAP/TAZ. There is a direct correlation between levels of YAP/TAZ and CYR61 in liver tissues of patients with high‐grade nonalcoholic steatohepatitis. Conclusions: Liver injury in mice and humans increases levels of YAP/TAZ/CYR61 in hepatocytes, thus attracting macrophages to the liver to promote inflammation and fibrosis.

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  • Ctgf is described to be strongly regulated during liver fibrosis.

    “The regulator gene of inflammation, the Ctgf gene, showed a tendency mainly in RT‐PCR; despite being described to be strongly regulated during liver fibrosis (Fig. S5D) [6, 7].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [6]

    The Results section reports CTGF expression in YAP-overexpressing mouse livers that subsequently developed fibrosis. However, the Discussion says the authors could not detect Ctgf among these ligands in a liver-injury setting with more modest YAP/TAZ activation. The paper therefore supports regulation in a specific experimental model, not a general claim that Ctgf is strongly regulated during liver fibrosis (page numbers unavailable). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • YAP/TAZ proteins have been involved in lipid metabolism in hepatocytes.

    “Also, YAP/TAZ proteins have been involved in lipid metabolism in hepatocytes [6].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [6]

    The Results section, “Chronic Liver Injury Leads to Elevated YAP/TAZ Activity” (page unavailable), reports increased hepatocyte YAP and TAZ in a lipodystrophic mouse model with features of NASH. The Discussion also links their elevation to lipotoxic injury. These passages connect YAP/TAZ to a lipid-related liver condition, but do not show that the proteins regulate lipid metabolism in hepatocytes. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • YAP/TAZ proteins were associated with fatty metabolism programmes in hepatocytes.

    “Interestingly, MRTFA KO has been associated with the resistance to develop steatosis [31], and YAP/TAZ proteins were associated with fatty metabolism programmes in hepatocytes [6]; however, there is important evidence about the role of MRTFs in lipid metabolism [53, 54].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [6]

    The Results section on hepatocyte gene expression programs (page unavailable) reports that metabolic programs differed between injured control and YAP/TAZ-knockout hepatocytes. The chronic-injury Results section also associates elevated hepatocyte YAP/TAZ with a lipodystrophy model of NASH. Neither passage identifies the affected programs specifically as fatty-metabolism programs, so that specificity is unsupported. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • This may imply a significant role of the hepatocytes in the response to mechanical modifications during liver fibrosis through MRTcoF.

    “This may imply a significant role of the hepatocytes in the response to mechanical modifications during liver fibrosis through MRTcoF, as suggested previously [5, 6].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [6]

    The Results section (‘Reduction in Hepatocyte YAP/TAZ Levels Attenuates Liver Inflammation and Fibrosis’; page unavailable) supports a role for hepatocyte YAP/TAZ signaling in liver fibrosis. Our copy does not establish that hepatocytes respond to mechanical modifications during fibrosis through MRTcoF; it examines injury and YAP/TAZ activity rather than that proposed mechanical response. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In hepatocytes, activation of YAP and TAZ cofactors has a fundamental role in the appropriate response to damage during liver fibrosis.

    “In hepatocytes, the activation of YAP and TAZ cofactors have a fundamental role in the appropriate response to damage during liver fibrosis [6, 20, 21].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [6]

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Authors
Mooring, M., Fowl, B. H., Lum, S. Z. C., Liu, Y., Yao, K., Softic, S., Kirchner, R., Bernstein, A., Singhi, A. D., Jay, D. G., Kahn, C. R., Camargo, F. D., & Yimlamai, D.
Affiliations
  • Children's Hospital of Pittsburgh (US)
  • Boston Children's Hospital (US)
  • Harvard University (US)
  • Tufts University (US)
  • University of Pittsburgh (US)
  • Joslin Diabetes Center (US)
Corresponding author
Yimlamai, Dean
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2020-01-03
Volume
71
Issue
5
Pages
1813-1830
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.30928
PMC
PMC7062580
OpenAlex
W2972904585
Cited by
162
References
48
Citations by year
2026: 16 · 2025: 30 · 2024: 25 · 2023: 26 · 2022: 28 · 2021: 20 · 2020: 16
FWCI
10.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA183119)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031036, R01DK031036, P30 DK 40561, R01DK099559, K08DK105351, R01DK033201, P30DK120531, P30DK036836, P30DK034854, P30DK040561)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB001026)
  • Center for Information Technology (UL1RR025758)
  • National Center for Research Resources (UL1RR025758)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD000850)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
YAP, TAZ, Hippo signaling pathway, liver fibrosis, liver inflammation, CYR61, chemokines, macrophage recruitment, hepatocyte-specific knockout, nonalcoholic steatohepatitis
MeSH terms
Loss of Function Mutation, Gain of Function Mutation, Collagen Type I, alpha 1 Chain, YAP-Signaling Proteins, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Animals, Disease Models, Animal, Humans, Liver Cirrhosis, Stress, Physiological, Transcription Factors, Trans-Activators, Cell Cycle Proteins, Hepatocytes, Adaptor Proteins, Signal Transducing, Mice, Cysteine-Rich Protein 61, Non-alcoholic Fatty Liver Disease

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