Pazienza Valerio, Borghesan Michela, Mazza Tommaso, Sheedfar Fareeba, Panebianco Concetta, Williams Roger, Mazzoccoli Gianluigi, Andriulli Angelo, Nakanishi Tomoko, Vinciguerra Manlio
Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
Aging (Albany NY). 2014 Jan;6(1):35-47. doi: 10.18632/aging.100632.
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.
非酒精性脂肪性肝病（NAFLD）包括与肝脏脂肪沉积相关的病症，这些病症在衰老过程中通常会恶化。MacroH2A1是组蛋白H2A的一种变体，是参与肿瘤发生过程和细胞衰老的关键转录调节因子，具有两种可变剪接异构体，即macroH2A1.1和macroH2A1.2。MacroH2A1.1与O-乙酰ADP核糖具有高亲和力结合，O-乙酰ADP核糖是一种由NAD+依赖性脱乙酰酶SIRT1催化的反应产生的小代谢物，而macroH2A1.2则不能。这种结合的功能意义尚不清楚。我们之前报道过，在NAFLD小鼠模型中，macroH2A1.1和macroH2A1.2的肝脏水平存在差异表达。在此我们表明，macroH2A1.1的过表达而非macroH2A1.2的过表达能够保护肝细胞免受脂质积累。过表达macroH2A1.1的细胞表现出改善的葡萄糖代谢、脂质生成基因表达降低以及脂肪酸含量降低。SIRT1/macroH2A1.1依赖性的脂质代谢表观遗传调控可能与NAFLD的发展有关。
