Induction of overlapping genes by fasting and a peroxisome proliferator in pigs: Evidence of functional PPARα in nonproliferating species

Department of Animal Sciences, University of Illinois, Urbana-Champaign, Urbana, Illinois, United States
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.11). 07/2005; 288(6):R1525-35. DOI: 10.1152/ajpregu.00751.2004
Source: PubMed


Peroxisome proliferator-activated receptor alpha (PPARalpha), a key regulator of fatty acid oxidation, is essential for adaptation to fasting in rats and mice. However, physiological functions of PPARalpha in other species, including humans, are controversial. A group of PPARalpha ligands called peroxisome proliferators (PPs) causes peroxisome proliferation and hepatocarcinogenesis only in rats and mice. To elucidate the role of PPARalpha in adaptation to fasting in nonproliferating species, we compared gene expressions in pig liver from fasted and clofibric acid (a PP)-fed groups against a control diet-fed group. As in rats and mice, fasting induced genes involved with mitochondrial fatty acid oxidation and ketogenesis in pigs. Those genes were also induced by clofibric acid feeding, indicating that PPARalpha mediates the induction of these genes. In contrast to rats and mice, little or no induction of genes for peroxisomal or microsomal fatty acid oxidation was observed in clofibric acid-fed pigs. Histology showed no significant hyperplasia or hepatomegaly in the clofibric acid-fed pigs, whereas it showed a reduction of glycogen by clofibric acid, an effect of PPs also observed in rats. Copy number of PPARalpha mRNA was higher in pigs than in mice and rats, suggesting that peroxisomal proliferation and hyperresponse of several genes to PPs seen only in rats and mice are unrelated to the abundance of PPARalpha. In conclusion, PPARalpha is likely to play a central role in adaptation to fasting in pig liver as in rats and mice.

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    • "Likewise, the present findings underscore that H group increased the expression of gene sets regulated by peroxisome proliferator-activated receptors alpha (PPAR-α) (APOA2, CYP2C9, CYP2C19) and RXR (ABCG8, CYP7A1) transcription factors, both of which are shown to have an important role in lipid homeostasis. For instance, PPAR-α is an important regulator of cellular fatty acid uptake and intracellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, and gluconeogenesis in several species [41-43], whereas RXR plays a crucial role in the transcriptional regulation of a spectrum of genes controlling cholesterol homeostasis and bile acid homeostasis, together with nuclear receptor FXR, a key transcription factor that regulates cholesterol 7 α-hydroxylase (CYP7A1) activity and mRNA levels. "
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    ABSTRACT: New advances in high-throughput technologies have allowed for the massive analysis of genomic data, providing new opportunities for the characterization of the transcriptome architectures. Recent studies in pigs have employed RNA-Seq to explore the transcriptome of different tissues in a reduced number of animals. The main goal of this study was the identification of differentially-expressed genes in the liver of Iberian x Landrace crossbred pigs showing extreme phenotypes for intramuscular fatty acid composition using RNA-Seq. The liver transcriptomes of two female groups (H and L) with phenotypically extreme intramuscular fatty acid composition were sequenced using RNA-Seq. A total of 146 and 180 unannotated protein-coding genes were identified in intergenic regions for the L and H groups, respectively. In addition, a range of 5.8 to 7.3% of repetitive elements was found, with SINEs being the most abundant elements. The expression in liver of 186 (L) and 270 (H) lncRNAs was also detected. The higher reproducibility of the RNA-Seq data was validated by RT-qPCR and porcine expression microarrays, therefore showing a strong correlation between RT-qPCR and RNA-Seq data (ranking from 0.79 to 0.96), as well as between microarrays and RNA-Seq (r=0.72). A differential expression analysis between H and L animals identified 55 genes differentially-expressed between groups. Pathways analysis revealed that these genes belong to biological functions, canonical pathways and three gene networks related to lipid and fatty acid metabolism. In concordance with the phenotypic classification, the pathways analysis inferred that linolenic and arachidonic acids metabolism was altered between extreme individuals. In addition, a connection was observed among the top three networks, hence suggesting that these genes are interconnected and play an important role in lipid and fatty acid metabolism. In the present study RNA-Seq was used as a tool to explore the liver transcriptome of pigs with extreme phenotypes for intramuscular fatty acid composition. The differential gene expression analysis showed potential gene networks which affect lipid and fatty acid metabolism. These results may help in the design of selection strategies to improve the sensorial and nutritional quality of pork meat.
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    • "The finding that these genes were up-regulated in the pigs fed the oxidized fat indicates an activation of PPARα in these pigs. Activation of PPARα in the liver induced by administration of oxidized fats has been established in rats and pigs [13,17,19,24], although the effect in pigs in this regard is less pronounced than in rodents due to the fact that pigs have generally a lower expression of PPARα and the response of many genes to PPARα activation in pigs is much lower than in rodents [25,26]. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21), whose expression is induced by peroxisome proliferator-activated receptor α (PPARα), has been recently identified as a novel metabolic regulator which plays a crucial role in glucose homeostasis, lipid metabolism, insulin sensitivity and obesity. Previous studies have shown that administration of oxidized fats leads to an activation of PPARα in the liver. Therefore, the present study investigated the hypothesis that feeding of oxidized fats causes an induction of FGF21 in the liver. Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h. In pigs fed the oxidized fat mRNA abundance and protein concentrations of FGF21 in liver were significantly increased (P < 0.05), and the protein concentrations of FGF21 in plasma tended to be increased (P < 0.1) in comparison to control pigs. Moreover, pigs fed the oxidized fat had increased transcript levels of the PPARα target genes acyl-CoA oxidase, carnitine palmitoyltransferase-1 and novel organic cation transporter 2 in the liver (P < 0.05), indicative of PPARα activation. The present study shows for the first time that administration of an oxidized fat induces the expression of FGF21 in the liver, probably mediated by activation of PPARα. Induction of FGF21 could be involved in several effects observed in animals administered an oxidized fat.
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    • "Regarding expression of PPARα, there is, however, a different tissue profile between pigs and rats. Expression of PPARα in the liver is much lower in pigs than in rodents (Cheon et al., 2005; Luci et al., 2007). In contrast, pigs have a considerable expression of PPARα in the white adipose tissue (Ding et al., 2000) while in rats it is nearly completely absent in adipose tissue (Escher et al., 2001). "
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