Role of SIRT1-FoxO1 Signaling in Dietary Saturated Fat-Dependent Upregulation of Liver Adiponectin Receptor 2 in Ethanol-Administered Mice

The aim of the present study is to examine the effects of dietary saturated fatty acids on liver adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) in ethanol-administered animals and in ethanol-exposed cultured hepatic cells, and to explore the underlying molecular mechanisms. The mRNA and protein levels of hepatic AdipoR2 were selectively increased by chronic ethanol feeding to mice consuming a diet high in saturated fat (HSF). Administration of an HSF diet blocked hyperacetylation of forkhead transcription factor 1 (FoxO1), a known target of sirtuin 1 (SIRT1), increased nuclear FoxO1 protein levels, and enhanced association of FoxO1 with the AdipoR2 promoter in the livers of ethanol-fed mice. Treatment of cultured hepatic cells with palmitic acid (a major saturated fatty acid in HSF diet) in the presence of ethanol robustly increased AdipoR2 mRNA expression and enhanced activity of a mouse AdipoR2 promoter. Knocking down SIRT1 or FoxO1 using the small silencing SIRT1 or FoxO1 plasmid blunted the palmitic acid effect. Taken together, these results reveal that dietary saturated fat selectively upregulates hepatic AdipoR2 through modulation of SIRT1-FoxO1 signaling in ethanol fed mice, and this effect may contribute to the protective effect of the HSF diet against alcoholic fatty liver. Antioxid. Redox Signal. 15, 425–435