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

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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

Bibliographical note

Funding Information:
Author contributions: H.W., K.H.K., and J.H.A. designed research; H.W., T.R., Y.J.W., J.L.L., B.T.K., A.M., L.L.S., M.S.R., A.N.L., T.C., J.C.M., and S.G. performed research; P.S. contributed new reagents/analytic tools; H.W., T.R., Y.J.W., J.S., S.R., A.H., A.N.L., T.W.M.F., U.A., K.H.K., and J.H.A. analyzed data; and J.H.A. wrote the paper. Competing interest statement: P.S. has been a consultant at Novartis, Genovis, Guide-point, The Planning Shop, ORIC Pharmaceuticals, and Exo Therapeutics; his laboratory receives research funding from Novartis. This article is a PNAS Direct Submission. Published under the PNAS license.

Funding Information:
We thank LeeAnn Higgins and Todd Markowski for help with proteomics analysis, the University of Pennsylvania Diabetes Research Center for the use of the Functional Genomics Core (P30 DK19525), Wendy S. Larson, and Susan K. Dachel from MVAHCS Pathology for performing immunostains. This work was supported by the NIH Grants R01DK54921 (to J.H.A.), R01DK102667 (to K.H.K.), R01DK98414, and R56112768 (to U.A.) and R01CA202634 (to P.S.). N.M.R. and M.S. were recorded using the Metabolism Shared Resources supported, in part, by NIH Grants P30CA177558 (to B. M. Evers) and 1U24DK097215-01A1 (to R. M. Higashi, T.W.M.F., and A.N.L.).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

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

PubMed: MeSH publication types

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

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