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 downregulated 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(ΔLiv)). Knockout mice were treated with
fibrates or fasted for 24 h to activate PPARα. Basal expression of the PPARα target genes Cyp4a10 and Cyp4a14 was reduced in
Sirt1(ΔLiv) mice compared with wild-type mice. However, no difference was observed between wild-type and
Sirt1(ΔLiv) 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(ΔLiv) mice were maintained on a high-fat diet for 14 wk, followed by
fibrate treatment.
Sirt1(ΔLiv) mice exhibited increased body mass compared with control mice. In the context of a high-fat diet,
Sirt1(ΔLiv) 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.