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Nutrition and Disease

Mammalian Sirtuin 1 Is Involved in the Protective Action of Dietary Saturated Fat against Alcoholic Fatty Liver in Mice^1,2

³ Departments of Molecular Pharmacology and Physiology and ⁴ Molecular Medicine, University of South Florida Health Sciences Center, Tampa, FL 33612

^* To whom correspondence should be addressed. E-mail: myou{at}health.usf.edu.

This study was undertaken to elucidate the mechanism underling the protective effect of a high saturated fat (HSF) diet against the development of alcoholic fatty liver in mice. We tested the effects of a HSF diet on the ethanol-mediated increase in hepatic sterol regulatory element binding protein 1 (SREBP-1) activity. Thirty-two male mice were divided into 4 groups and fed liquid diets consisting of either a high polyunsaturated fat (40% of energy from corn oil) or a HSF (40% of energy from cocoa butter) diet with or without ethanol for 4 wk. In the ethanol-containing diets, ethanol was substituted for an equivalent amount of carbohydrate to provide 27.5% of the total energy. Control mice were pair-fed the same volume of liquid diets as the ethanol-fed mice. The HSF diet suppressed the increase in mature SREBP-1 protein and prevented increased mRNA of the SREBP-1-regulated lipogenic enzymes in the ethanol-fed mice (P < 0.05). Sirtuins 1 (SIRT1), a NAD⁺-dependent class III histone deacetylase, was upregulated by ethanol administration in mice fed the HSF diet (P < 0.05). The HSF diet blocked histone H3 at lysine 9 (lys9) hyperacetylation and attenuated association of acetylated histone H3-Lys9 with the promoters of mitochondrial glycerol-3-phosphate acyltransferase and stearoyl-CoA desaturase 1 in the livers of the ethanol-fed mice. These results suggest that the protective effects of HSF diet against the development of alcoholic liver steatosis may occur via regulation of the hepatic SIRT1-SREBP-1-histone H3 axis, suppressing the expression of genes encoding lipogenic enzymes and slowing the synthesis of hepatic fatty acids.

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