Differential Regulation of Peroxisome Proliferator-Activated Receptor (PPAR)-α1 and Truncated PPARα2 as an Adaptive Response to Fasting in the Control of Hepatic Peroxisomal Fatty Acid β-Oxidation in the Hibernating Mammal

Seasonal obesity and fasting-associated hibernation are the two major metabolic events governing hepatic lipid metabolism in hibernating mammals. In this process, however, the role of the nuclear receptor known as peroxisome proliferator-activated receptor (PPAR)-alpha has not been elucidated yet. Here we show, as in human, that jerboa (Jaculus orientalis) liver expresses both active wild-type PPAR alpha(PPAR alpha 1wt) and truncated PPAR alpha forms and that the PPAR alpha 1wt to truncated PPAR alpha 2 ratio, which indicates the availability of active PPAR alpha 1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPAR alpha, during prehibernating and hibernating states, was demonstrated by the induction of its target genes, which encode peroxisomal proteins such as acyl-CoA oxidase 1, peroxisomal membrane protein 70, and catalase, accompanied by a concomitant induction of PPAR alpha thermogenic coactivator PPAR alpha coactivator-1 alpha. Interestingly, sustained activation of PPAR alpha by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPAR alpha during prehibernation and overinduces its target genes, disrupting the prehibernation fattening process. In striking contrast, during fasting-associated hibernation, jerboas exhibit preferential up-regulation of hepatic peroxisomal fatty acid oxidation instead of the mitochondrial pathway, which is down-regulated. Taken together, our results strongly suggest that PPAR alpha is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPAR alpha and the activation of its target genes during hibernation bouts of jerboas. (Endocrinology 150: 1192-1201, 2009)