ArticleHepatology (Baltimore, Md.)2021
Yes-Associated Protein Is Crucial for Constitutive Androstane Receptor-Driven Hepatocyte Proliferation But Not for Induction of Drug Metabolism Genes in Mice.
Article in Hepatology (Baltimore, Md.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration.Cellular and molecular gastroenterology and hepatology · 2026Article
- Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.The American journal of pathology · 2026Article
- Constitutive androstane receptor, liver pathophysiology and chemical contaminants: current evidence and perspectives.Frontiers in endocrinology · 2025Review
- Constitutive androstane receptor (CAR) functions as a tumor suppressor via regulating stemness in liver cancer.Scientific reports · 2024Article
- Direct mechanical exposure initiates hepatocyte proliferation.JHEP reports : innovation in hepatology · 2023Article
- Single-cell transcriptomics implicates the FEZ1-DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence.Cell proliferation · 2023Article
- CAR requires Gadd45β to promote phenobarbital-induced mouse liver tumors in early stage.Frontiers in oncology · 2023Article
- ZO-2/Tjp2 suppresses Yap and Wwtr1/Taz-mediated hepatocyte to cholangiocyte transdifferentiation in the mouse liver.NPJ Regenerative medicine · 2022Article
- Dysregulation of Lipid and Glucose Homeostasis in Hepatocyte-Specific SLC25A34 Knockout Mice.The American journal of pathology · 2022Article
- Lymphocyte-Specific Protein-1 Suppresses Xenobiotic-Induced Constitutive Androstane Receptor and Subsequent Yes-Associated Protein-Activated Hepatocyte Proliferation.The American journal of pathology · 2022Article
- YAP-TEAD mediates PPAR α-induced hepatomegaly and liver regeneration in mice.Hepatology (Baltimore, Md.) · 2022Article
- Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors.Cell reports · 2021Article
- The xenobiotic receptors PXR and CAR in liver physiology, an update.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND AND
aimsConstitutive androstane receptor (CAR) agonists, such as 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size, including that of liver. Our and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP treatment in mice and the potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and hepatocyte proliferation using hepatocyte-specific Yap-knockout (KO) mice. APPROACH AND
resultsAdeno-associated virus 8-thyroxine binding globulin promoter-Cre recombinase vector was injected to Yap-floxed mice for achieving hepatocyte-specific Yap deletion followed by TCPOBOP treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including cytochrome P450 [Cyp] 2b10, Cyp2c55, and UDP-glucuronosyltransferase 1a1 [Ugt1a1]). However, Yap deletion substantially reduced TCPOBOP-induced hepatocyte proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice because of delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma protein. Furthermore, the induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2, and B1), and important mitotic regulators (such as Aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes that were mainly related to proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these proliferation genes through alerting expression of Myc and forkhead box protein M1, two critical transcriptional regulators of CAR-mediated hepatocyte proliferation.
conclusionsOur study revealed an important role of Yap signaling in CAR-driven hepatocyte proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.
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