ArticleProceedings of the National Academy of Sciences of the United States of America2020
A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 55 citations in OpenAlex.
- TERT drives liver tumorigenesis beyond telomere elongation.Life science alliance · 2026Article
- Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver.bioRxiv : the preprint server for biology · 2026Article
- The Wnt/β-catenin-P2-HNF4α feedback loop facilitates colorectal tumorigenesis and malignancy.Journal of translational medicine · 2025Article
- Article
- Hepatocyte nuclear factor 4-Alpha: a key regulator in liver carcinogenesis.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- Hepatocytes as Model for Investigating Natural Senotherapeutic Compounds and Their Effects on Cell Cycle Dynamics and Genome Stability.International journal of molecular sciences · 2025Review
- Breaking the rules of cell biology: Lessons from the liver's exceptional regenerative capacity.Molecular biology of the cell · 2025Review
- Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics.Signal transduction and targeted therapy · 2025Review
- Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.Cell reports · 2025Article
- Low Dose of Nickel and Benzo [a] Anthracene in Rat-Diet, Induce Apoptosis, Fibrosis, and Initiate Carcinogenesis in Liver via NF-Ƙβ Pathway.Biological trace element research · 2025Article
- MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/β-catenin signaling.Cell death & disease · 2024Article
- The interplay of transition metals in ferroptosis and pyroptosis.Cell division · 2024Review
- Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.The Journal of biological chemistry · 2023Article
- Direct mechanical exposure initiates hepatocyte proliferation.JHEP reports : innovation in hepatology · 2023Article
- Review
- Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation.Science signaling · 2023Article
- HNF4α is possibly the missing link between epithelial-mesenchymal transition and Warburg effect during hepatocarcinogenesis.Cancer science · 2023Article
- Microfibril-associated protein 2 is activated by POU class 2 homeobox 1 and promotes tumor growth and metastasis in tongue squamous cell carcinoma.Human cell · 2023Article
- HNF4α isoforms: the fraternal twin master regulators of liver function.Frontiers in endocrinology · 2023Review
- Article
Corrections and comments
- Erratum issued
Authors and funding
20 authors at 6 institutions in 1 country.
Funding
Abstract
Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of liver function and a tumor suppressor in hepatocellular carcinoma (HCC). In this study, we explore the reciprocal negative regulation of HNF4α and cyclin D1, a key cell cycle protein in the liver. Transcriptomic analysis of cultured hepatocyte and HCC cells found that cyclin D1 knockdown induced the expression of a large network of HNF4α-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4α to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4α deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4α maintains proliferative quiescence in the liver, at least, in part, via repression of cyclin D1. Acute cyclin D1 deletion in the regenerating liver markedly inhibited hepatocyte proliferation after partial hepatectomy, confirming its pivotal role in cell cycle progression in this in vivo model, and enhanced the expression of HNF4α target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4α-dependent fashion), indicating that the cyclin D1-HNF4α axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4α was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4α coordinately controls the cell cycle machinery and metabolism in the liver.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.