Hepatic sirtuin 1 is dispensable for fibrate- induced peroxisome proliferator-activated receptor-α function in vivo

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) mediates metabolic remodeling, resulting in enhanced mitochondrial and peroxisomal beta-oxidation of fatty acids. In addition to the physiological stimuli of fasting and high-fat diet, PPAR alpha is activated by the fibrate class of drugs for the treatment of dyslipidemia. Sirtuin 1 (SIRT1), an important regulator of energy homeostasis, was downregulated in fibrate-treated wild-type mice, suggesting PPAR alpha regulation of Sirt1 gene expression. The impact of SIRT1 loss on PPAR alpha functionality in vivo was assessed in hepato-cyte-specific knockout mice that lack the deacetylase domain of SIRT1 (Sirt1(triangle Liv)). Knockout mice were treated with fibrates or fasted for 24 h to activate PPAR alpha. Basal expression of the PPAR alpha target genes Cyp4a10 and Cyp4a14 was reduced in Sirt1(triangle Liv) mice compared with wild-type mice. However, no difference was observed between wild-type and Sirt1(triangle Liv) mice in either fasting-or fibrate-mediated induction of PPAR alpha target genes. Similar to the initial results, there was no difference in fibrate-activated PPAR alpha gene induction. To assess the relationship between SIRT1 and PPAR alpha in a pathophysiological setting, Sirt1(triangle Liv) mice were maintained on a high-fat diet for 14 wk, followed by fibrate treatment. Sirt1(triangle Liv) mice exhibited increased body mass compared with control mice. In the context of a high-fat diet, Sirt1(triangle Liv) mice did not respond to the cholesterol-lowering effects of the fibrate treatment. However, there were no significant differences in PPAR alpha target gene expression. These results suggest that, in vivo, SIRT1 deacetylase activity does not significantly impact induced PPAR alpha activity.