Recent studies have shown that dietary oxidised fats influence the lipid metabolism in rats by activation of PPARa. In this study, we investigated whether a mildly oxidised fat causes activation of PPARa in pigs which are non-proliferators like man. Eighteen pigs were assigned to two groups and received either a diet containing 90 g/kg of a fresh fat or the same diet with 90 g/kg of an oxidised fat prepared by heating for 24 h at 1808C in a deep fryer. Pigs fed the oxidised fat had a higher peroxisome count, a higher activity of catalase and a higher mRNA concentration of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in the liver and a higher concentration of 3-hydroxybutyrate in plasma than pigs fed the fresh fat (P, 0·05). Hepatic mRNA concentrations of acyl-CoA oxidase and carnitine palmitoyltransferase-1 tended to be increased in pigs fed the oxidised fat compared to pigs fed the fresh fat (P,0·10). Pigs fed the oxidised fat, moreover, had higher mRNA concentrations of sterol regulatory elementbinding protein (SREBP)-1 and its target genes acetyl-CoA carboxylase and stearoyl-CoA desaturase in the liver and higher mRNA concentrations of SREBP-2 and its target genes 3-hydroxy-3-methylglutary-CoA reductase and LDL receptor in liver and small intestine. In conclusion, this study shows that even a mildly oxidised fat causes activation of PPARa in the liver of pigs. Up-regulation of SREBP and its target genes in liver and small intestine suggests that the oxidised fat could stimulate synthesis of cholesterol and TAG in these tissues. The typical western diet contains large quantities of PUFA that are heated or processed to varying degrees. In fast-food restaurants fat is heated in fryers for up to 18 h daily, at temperatures close to 1808C (Frankel et al. 1984). Several studies with animals have been performed to investigate the effects of oxidised fats on the metabolism (reviewed in Cohn, 2002). Recently, it has been shown in rats that oxidised fats are able to influence the lipid metabolism by activation of PPARa (Chao et al. , 2004(Chao et al. , 2005Sülzle et al. 2004), a transcription factor belonging to the nuclear hormone receptor superfamily (Schoonjans et al. 1996). This is probably due to the occurrence of hydroxy-and hydroperoxy fatty acids such as hydroxy octadecadienoic acid and hydroperoxy octadecadienoic acid which are potent activators of PPARa (Delerive et al. 2000;Mishra et al. 2004;. Activation of PPARa leads to an increase in the transcription of genes related to fatty acid transport across the cell membrane, intracellular lipid trafficking, mitochondrial and peroxisomal fatty acid uptake, and both mitochondrial and peroxisomal fatty acid b-oxidation, gluconeogenesis and ketogenesis (Mandard et al. 2004). Recently, it has been shown that PPARa activation influences also the expression or the proteolytic activation of sterol regulatory element-binding proteins (SREBP), transcription factors which control fatty acid synthesis and cholesterol homeostasis (Patel et al. 2001;Guo et al. 2001;K...

This study investigated the effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor (PPAR)-alpha and various genes of the lipid metabolism in liver and adipose tissue of pigs. An experiment with 18 pigs was performed in which pigs were fed either a control diet or the same diet supplemented with 5 g clofibrate/kg for 28 days. Pigs treated with clofibrate had heavier livers, moderately increased mRNA concentrations of various PPAR-alpha target genes in liver and adipose tissue, a higher concentration of 3-hydroxybutyrate, and markedly lower concentrations of triglycerides and cholesterol in plasma and lipoproteins than control pigs (P < 0.05). mRNA concentrations of sterol regulatory element-binding proteins (SREBP)-1 and -2, insulin-induced genes (Insig)-1 and Insig-2, and the SREBP target genes acetyl-CoA carboxylase, 3-methyl-3-hydroxyglutaryl-CoA reductase, and low-density lipoprotein receptor in liver and adipose tissue and mRNA concentrations of apolipoproteins A-I, A-II, and C-III in the liver were not different between both groups of pigs. In conclusion, this study shows that clofibrate treatment activates PPAR-alpha in liver and adipose tissue and has a strong hypotriglyceridemic and hypocholesterolemic effect in pigs. The finding that mRNA concentrations of some proteins responsible for the hypolipidemic action of fibrates in humans were not altered suggests that there were certain differences in the mode of action compared with humans. It is also shown that PPAR-alpha activation by clofibrate does not affect hepatic expression of SREBP target genes involved in synthesis of triglycerides and cholesterol homeostasis in liver and adipose tissue of pigs.

Background: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro-and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species.