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