SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation.
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.
Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
Valerio
V
Pazienza
Michela
M
Borghesan
Tommaso
T
Mazza
Fareeba
F
Sheedfar
Concetta
C
Panebianco
Roger
R
Williams
Gianluigi
G
Mazzoccoli
Angelo
A
Andriulli
Tomoko
T
Nakanishi
Manlio
M
Vinciguerra
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008112:Liver Glycogen / Q000096:biosynthesis; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D038961:O-Acetyl-ADP-Ribose / Q000378:metabolism*; D011485:Protein Binding; D056564:Sirtuin 1 / Q000378:metabolism*; D014162:Transfection
D005227:Fatty Acids; D006657:Histones; D008112:Liver Glycogen; D038961:O-Acetyl-ADP-Ribose; C120756:macroH2A histone; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose