Hepatic sirtuin 1 is dispensable for fibrate-induced peroxisome proliferator-activated receptor-α function in vivo.
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.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
Jessica A
JA
Bonzo
Chad
C
Brocker
Changtao
C
Jiang
Rui-Hong
RH
Wang
Chu-Xia
CX
Deng
Frank J
FJ
Gonzalez
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D058607:Fibric Acids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D056564:Sirtuin 1 / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D058607:Fibric Acids; D047493:PPAR alpha; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
fibrates; peroxisome proliferator-activated receptor-α; sirtuin 1