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

Abstract

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 PPARalpha (PPARalpha1wt) and truncated PPARalpha forms and that the PPARalpha1wt to truncated PPARalpha2 ratio, which indicates the availability of active PPARalpha1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPARalpha, 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 PPARalpha thermogenic coactivator PPARgamma coactivator-1alpha. Interestingly, sustained activation of PPARalpha by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPARalpha 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 PPARalpha is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPARalpha and the activation of its target genes during hibernation bouts of jerboas.

Shotgun Proteomics Analysis of Hibernating Arctic Ground Squirrels

“…ACADM and ACADL, acting on medium and long chained fatty acids, respectively, however, were not differentially expressed in our study. El Kebbaj et al (35) observed that the activity of ACADM decreased in the livers of hibernating jerboa (Jaculus orientalis) compared with euthermic active animals but increased compared with prehibernating animals. Epperson et al (15) showed that ACADL was significantly overexpressed in the livers of thirteen-lined ground squirrel in Ent versus SA.…”

“…The critical threshold (C T ) value is the PCR cycle number where the PCR growth curve crosses a defined threshold in the linear range of the reaction. Gene expression values can be calculated from C T by the formula: 2 35 Ϫ CT . In every real time PCR assay, 18S rRNA was used as the control for significant bias of starting materials across samples.…”

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

“…PPAR is regulated also by repressive post-trascriptional mechanisms such as -PPAR 2, a A truncated isoform resulting from a posttranslational exon skipping [39] -post-translational modifications such as phosphorylation, [40][41][42].…”

To be or not to be: the regulation of mRNA fate as a survival strategy during mammalian hibernation

“…The peroxisome proliferatoractivated receptor (PPAR) family of transcription factors play a key role in lipid metabolism, and controlled regulation of lipid metabolism is integral to mammalian hibernation (Eddy et al 2005b). While PPARgamma and the PPARgamma coactivator (PGC-1alpha) have been shown to respond to hibernation in thirteen-lined ground squirrels (Eddy et al 2005b), PPARα also plays a role in J. orientalis liver during hibernation (El Kebbaj et al 2009). The data showed that jerboa liver expressed an active wild-type form of PPARα (PPARα1wt) and a truncated PPARα (PPARα2tr), and the ratio of wt:tr was differentially regulated during hibernation.…”

“…Taken together, mammalian hibernators are subject to substantial transcriptional and posttranscriptional regulation, and various mechanisms have been elucidated to date (Storey and Storey 2004b). For example, work spanning a range of mammalian hibernators has identified epigenetic controls that coordinate the global suppression of transcription (Morin and Storey 2009), the involvement of transcription factors, and their role in achieving a directed cellular response to the various stresses faced as a result of hibernation (Carey et al 2000;Cai et al 2004;Lee et al 2007;Mamady and Storey 2008;Morin et al 2008b;El Kebbaj et al 2009;Tessier and Storey 2012), microRNAs which exert reversible control over translation (Morin et al 2008a;Liu et al 2010;Kornfeld et al 2012), posttranslational modifications which influence the formation of the 48S preinitiation complex (Wu and Storey 2012;Van Breukelen et al 2004), and the disaggregation of polyribosomes during hibernation (Knight et al 2000;Hittel and Storey, 2002;Pan and Van Breukelen 2011).…”