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

Valerio Pazienza, Michela Borghesan, Tommaso Mazza, Fareeba Sheedfar, Concetta Panebianco, Roger Williams, Gianluigi Mazzoccoli, Angelo Andriulli, Tomoko Nakanishi, Manlio Vinciguerra

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)35-47
Number of pages13
JournalAging
Volume6
Issue number1
Publication statusPublished - Jan 2014

Keywords

  • Gene expression
  • Hepatocyte
  • Histone macroH2A1
  • Lipids

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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