Research Paper Volume 6, Issue 1 pp 35—47

SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation

Valerio Pazienza1, , Michela Borghesan1,2, , Tommaso Mazza3, , Fareeba Sheedfar4, , Concetta Panebianco1, , Roger Williams5, , Gianluigi Mazzoccoli2, , Angelo Andriulli1, , Tomoko Nakanishi6, , Manlio Vinciguerra1,7,8, ,

  • 1 Department of Medical Sciences, Gastroenterology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
  • 2 Department of Medical Sciences, Division of Internal Medicine, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
  • 3 Bioinformatics Unit, IRCCS “Casa Sollievo della Sofferenza” - Mendel Laboratory, Rome, Italy
  • 4 University of Groningen, University Medical Center Groningen (UMCG), Molecular Genetics, Groningen, The Netherlands
  • 5 Institute of Hepatology, Foundation for Liver Research, London, UK
  • 6 Division of Molecular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan
  • 7 University College London (UCL) – Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
  • 8 Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy

Received: December 9, 2013       Accepted: January 26, 2014       Published: January 28, 2014      

https://doi.org/10.18632/aging.100632
How to Cite

Abstract

Non-alcoholic-fatty-liver-disease (NAFLD) encompasses conditions associated to fat deposition in the liver, which are generally deteriorated during the aging process. MacroH2A1, a variant of histone H2A, is a key transcriptional regulator involved in tumorigenic processes and cell senescence, and featuring two alternatively splicing isoforms, macroH2A1.1 and macroH2A1.2. MacroH2A1.1 binds with high affinity O-acetyl ADP ribose, a small metabolite produced by the reaction catalysed by NAD+-dependent deacetylase SIRT1, whereas macroH2A1.2 is unable to do so. The functional significance of this binding is unknown. We previously reported that the hepatic levels of macroH2A1.1 and macroH2A1.2 are differentially expressed in mice models of NAFLD. Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation. MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content. SIRT1/macroH2A1.1-dependent epigenetic regulation of lipid metabolism may be relevant to NAFLD development.

Abbreviations

NAFLD: nonalcoholic-fatty-liver-disease; NASH: nonalcoholic steatohepatitis; TG: triglycerides; TC: total cholesterol; HCC: hepatocellular carcinoma; ORO: Oil red O; FFA: free fatty acids; UFA: unsaturated fatty acids; FA: fatty acids.