A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver

Heng Wu, Tzachi Reizel, Yue J. Wang, Jessica L. Lapiro, Betsy T. Kren, Jonathan Schug, Shilpa Rao, Ashleigh Morgan, Adam Herman, Laurie L. Shekels, Matthew S. Rassette, Andrew N. Lane, Teresa Cassel, Teresa W.M. Fan, Juan C. Manivel, Sumedha Gunewardena, Udayan Apte, Piotr Sicinski, Klaus H. Kaestner, Jeffrey H. Albrecht

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)17177-17186
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number29
DOIs
StatePublished - Jul 21 2020

Keywords

  • Cell cycle
  • Glycogen
  • Liver regeneration
  • Partial hepatectomy
  • Pyruvate carboxylase

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Fingerprint Dive into the research topics of 'A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver'. Together they form a unique fingerprint.

Cite this