| First Author | Wu H | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 29 | Pages | 17177-17186 |
| PubMed ID | 32631996 | Mgi Jnum | J:292265 |
| Mgi Id | MGI:6447710 | Doi | 10.1073/pnas.2002898117 |
| Citation | Wu H, et al. (2020) A negative reciprocal regulatory axis between cyclin D1 and HNF4alpha modulates cell cycle progression and metabolism in the liver. Proc Natl Acad Sci U S A 117(29):17177-17186 |
| abstractText | Hepatocyte nuclear factor 4alpha (HNF4alpha) 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 HNF4alpha 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 HNF4alpha-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4alpha to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4alpha deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4alpha 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 HNF4alpha target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4alpha-dependent fashion), indicating that the cyclin D1-HNF4alpha axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4alpha was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4alpha coordinately controls the cell cycle machinery and metabolism in the liver. |
