Introduction Hepatic steatosis is a major risk factor for the development of severe liver damage, including fibrosis, cirrhosis and hepatocellular carcinoma. It often exists as a co-morbidity factor with diabetes type I/II and with other manifestations of the metabolic syndrome. Recent studies highlight the importance of an epigenetic basis for the development of steatosis based on macroH2A1. MacroH2A1 is a histone variant of histone H2A, which possesses an additional protein domain called macro. When incorporated into the chromatin of hepatocytes, macroH2A1 regulates gene expression. Two alternatively spliced isoforms of macroH2A1 exist, which have been shown to be markers of breast, skin and lung cancer. Whole-body knock out of macroH2A1 in mice induces glucose intolerance and changes in genes regulating hepatic lipid metabolism. However, overt hepatic steatosis was not observed and the significance of these findings is unclear. We hypothesised that macroH2A1 could be involved in the pathogenesis of hepatic steatosis induced in the high fat-diet mouse model of metabolic syndrome.
Methods Wild type and homozygous knock-out male mice were placed on a high fat diet (Western diet, 42% of energy intake from saturated fats) for 8 weeks. At the end of the treatment, measurement of insulin sensitivity and glucose tolerance (ITT and GTT) were performed. Mice were sacrificed, and plasma and liver tissue harvested for further assays, including protein, gene expression and immunohistochemistry analyses.
Results Deterioration in insulin resistance and glucose intolerance induced by high fat diet was observed in macroH2A1 knock-out mice, compared to wild type littermates. Moreover, lack of macroH2A1 in mice significantly worsened the increase in circulating non-esterified fatty acids (NEFA) and the hepatic intracellular content of tryglicerides induced by high fat diet. Gene expression studies unveiled an increase in the hepatic expression of lipoprotein lipase (Lpl) and fatty acid transporter CD36 in knock-out mice.
Conclusion MacroH2A1 is a regulator of hepatic fat accumulation and its absence worsens hepatic steatosis and systemic imbalances upon a high fat regimen in mice. This could be due to a direct effect of macroH2A1 on chromatin structure and on the expression of key genes involved in liver lipid metabolism.
Competing interests None declared.
References 1. Changolkar LN, Costanzi C, Leu NA, et al. Developmental changes in histone macroH2A1-mediated gene regulation. Mol Cell Biol 2007;27:2758–64.
2. Boulard M, Storck S, Cong R, et al. Histone variant macroH2A1 deletion in mice causes female-specific steatosis. Epigenetics Chromatin. 2010;3:8.
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