| First Author | Bonzo JA | Year | 2014 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 306 |
| Issue | 7 | Pages | E824-37 |
| PubMed ID | 24496310 | Mgi Jnum | J:212297 |
| Mgi Id | MGI:5578441 | Doi | 10.1152/ajpendo.00175.2013 |
| Citation | Bonzo JA, et al. (2014) Hepatic sirtuin 1 is dispensable for fibrate-induced peroxisome proliferator-activated receptor-alpha function in vivo. Am J Physiol Endocrinol Metab 306(7):E824-37 |
| abstractText | Peroxisome proliferator-activated receptor-alpha (PPARalpha) 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, PPARalpha 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 PPARalpha regulation of Sirt1 gene expression. The impact of SIRT1 loss on PPARalpha functionality in vivo was assessed in hepatocyte-specific knockout mice that lack the deacetylase domain of SIRT1 (Sirt1(DeltaLiv)). Knockout mice were treated with fibrates or fasted for 24 h to activate PPARalpha. Basal expression of the PPARalpha target genes Cyp4a10 and Cyp4a14 was reduced in Sirt1(DeltaLiv) mice compared with wild-type mice. However, no difference was observed between wild-type and Sirt1(DeltaLiv) mice in either fasting- or fibrate-mediated induction of PPARalpha target genes. Similar to the initial results, there was no difference in fibrate-activated PPARalpha gene induction. To assess the relationship between SIRT1 and PPARalpha in a pathophysiological setting, Sirt1(DeltaLiv) mice were maintained on a high-fat diet for 14 wk, followed by fibrate treatment. Sirt1(DeltaLiv) mice exhibited increased body mass compared with control mice. In the context of a high-fat diet, Sirt1(DeltaLiv) mice did not respond to the cholesterol-lowering effects of the fibrate treatment. However, there were no significant differences in PPARalpha target gene expression. These results suggest that, in vivo, SIRT1 deacetylase activity does not significantly impact induced PPARalpha activity. |
