Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes
Abstract
Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEA domain family member (TEAD). In mouse livers, 1,4-bis-(2-[3,5-dichloropyridyloxy])benzene (TCPOBOP) (a mouse CAR [mCAR] activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared with mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mCAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induc…
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CAR's pro-proliferative role in liver is mediated through induction of c-Myc, Foxm1, and cyclin D1, and modulation of β-catenin and YAP signaling pathways.
“Prior studies have focused primarily on the pro-proliferative role of CAR in the liver, mediated through the induction of factors such as cellular-myelocytomatosis oncogene (c-Myc),15 forkhead box m1 (Foxm1),15 and cyclin D1 (Ccnd1),16 as well as modulation of β-catenin17,18 and Yes-associated protein19, 20, 21, 22 signaling pathways.”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [21]
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References 46 · Cited by 36
- Authors
- Abe, T., Amaike, Y., Shizu, R., Takahashi, M., Kano, M., Hosaka, T., Sasaki, T., Kodama, S., Matsuzawa, A., & Yoshinari, K.
- Affiliations
- Shizuoka University (JP)
- Tohoku University (JP)
- Corresponding author
- Yoshinari, Kouichi
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-06-08
- Volume
- 165
- Issue
- 2
- Pages
- 408-419
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2807576427
- Cited by
- 36
- References
- 46
- Citations by year
- 2026: 1 · 2025: 6 · 2023: 3 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 2
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Sciences and Technology of Japan (22390027, 24659061)
- Ministry of Economy, Trade and Industry of Japan, and Takeda Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- constitutive androstane receptor, YAP, TEAD, hepatocyte proliferation, liver hypertrophy, TCPOBOP, verteporfin, hepatocarcinogenesis, cell cycle genes
- MeSH terms
- Verteporfin, Constitutive Androstane Receptor, YAP-Signaling Proteins, Animals, Cells, Cultured, Hypertrophy, Liver, Male, Mice, Inbred C57BL, Phosphoproteins, Pyridines, Gene Expression, Receptors, Cytoplasmic and Nuclear, Cell Cycle Proteins, Hepatocytes, Adaptor Proteins, Signal Transducing, Cell Proliferation, Primary Cell Culture
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