Sirt1 mediates the effects of a short-term high-fat diet on the heart

High-fat diet leads to development of cardiac dysfunction through molecular mechanisms poorly known. The aim of this study is to elucidate the early events in cardiac dysfunction caused by a high-fat diet, before massive alterations due to obesity and indirect mechanisms of heart damage take place. Moreover, we analyzed the role of Sirt1, a major mediator of cardiac gene regulation, in these effects. Short-term high-fat feeding (5 weeks) caused a similar mild increase in body weight and triglyceridaemia in wild-type (wt) and Sirt1+/− mice. The high-fat diet suppressed the expression of lipid catabolism (PPARα target) gene expression in the hearts of wt mice, but not Sirt1+/− mice. Pro-inflammatory genes were induced and estrogen-related receptor-alpha (ERRα) target genes was suppressed in the hearts of wt fed the high-fat diet, but not in Sirt1+/− mice. We found the formation of a complex between PPARα and Sirt1 in wt mice under high-fat diet conditions which might account for suppression of the ERRα pathway. Sirt1 haploinsufficiency impairs the formation of this complex and promotes the binding of PPARα to the p65 subunit of NF-κB, thereby mediating inhibition of pro-inflammatory pathways and induction of PPARα target genes. Short-term high-fat diet causes metabolic and inflammatory alterations in heart, and Sirt1 is critical for mediating these cardiac alterations. The capacity of Sirt1 to interact with transcriptional regulators such as NF-κB and PPARα appears to be involved in the cardiac responsiveness to a high-fat diet.