Hyperlipidic diets induce early alterations of the vitamin A signalling pathway in rat colonic mucosa.

OBJECTIVE: Dietary factors can be associated with colorectal cancer. Fatty acids modulate gene expression in various tissues, mediated by activation of the peroxisome proliferator activated receptor: PPAR. Vitamin A signalling is mediated by retinoic acid (RA) receptors (RAR) and retinoid X receptors (RXR). The steroid nuclear receptors PPAR, RAR, RXR, are DNA-binding proteins and they induce gene transcription upon activation by specific ligands and interacting with distinct promoter sequences in the target genes. The aim of this study was to investigate the impact of hyperlipidic diets on the expression of PPARg, RXRa and RARb mRNA in rat colon. METHODS: Rats were fed during 4 weeks with the following diets: a cafeteria diet where 60% of the energy was supplied as lipids and a high fat diet (HFD) represented by 25% of a safflower oil (w/w) rich in polyunsaturated fatty acids, mainly n-6. Nuclear receptors mRNA were quantified by realtime RT-PCR with TaqMan probe process or SYBRGreen I chemical. RESULTS: The cafeteria diet and the HFD induced a significant decrease in RARb mRNA: -36% (p<0.02) and -64% (P<0.001) respectively. Simultaneously, an increased expression of PPARg mRNA was observed for cafeteria diet +35% (P<0.05) and for HFD +45% (P<0.05). The level of RXRa mRNA was significantly increased for cafeteria diet: +53% (P<0.0002), while no significant difference in RXRa mRNA was observed in colonic mucosa rats whose fed with the 25% HFD. CONCLUSIONS: These results showed that an hyperlipidic diet could induce early modifications in the pattern of expression of nuclear receptors in rat colon. Many mechanisms could be probably involved but one hypothesis is that a modification of the balance between the nuclear receptors, resulting from an increased expression of PPARg, could induce a decreased expression of RARb in rat colon.

Effect of a pharmacological activation of PPAR on the expression of RAR and TR in rat liver.

It has recently been shown that high-fat diets induce the expression of peroxisome proliferator-activated receptor (PPAR) with a concomitant decrease in expression of retinoic acid (RAR) and triiodothyronine (TR) receptors in rat liver. The authors have suggested that PPAR activation may be responsible for these modifications in nuclear receptor expression. With the aim of gaining further insight into a possible relationship between the patterns of expression of these receptors, we have examined, using a pharmacological model, the effect of a strong and specific PPAR activation induced by bezafibrate, a peroxisome proliferator agent. Activation of PPAR was evaluated by quantifying PPARalpha mRNA and acyl-CoA oxidase mRNA. The expression of RAR and TR was determined by assaying the binding properties of these nuclear receptors and by quantifying the mRNA level of RARbeta and TRalpha1,beta1 isoforms. After a 10 day treatment of young rats, induction of PPAR (PPARalpha mRNA was increased by 40% [P < 0.05 and acyl-CoA oxidase mRNA by 411% [P<0.001]) and a concomitant decrease of RAR and TR expression (Maximal Binding Capacity was decreased by 21 and 26%, respectively [P<0.05]) in the liver was observed. RXRalpha mRNA expression was unchanged by treatment. Cross-talk between RAR, TR and PPAR signalling pathways may be implicated in the new patterns of nuclear receptor expression observed. The decreased expression of RAR and TR reported here could provide a novel element for the understanding of the link between PPAR and tumorigenesis in rat liver.

Exposure to an obesity-inducing diet early affects the pattern of expression of peroxisome proliferator, retinoic acid, and triiodothyronine nuclear receptors in the rat.

Since evidence has appeared that alpha and gamma isoforms of the peroxisome proliferator receptors (PPARs) are involved in the regulation of triglyceride homeostasis and in the control of the differentiation of adipocytes that is required for the development of obesity, a large number of studies have investigated the physiologic role of nuclear receptors in the control of energy balance. The aim of this study was to determine the early effects of an obesity-inducing diet on the expression of PPAR alpha and gamma and other nuclear receptors such as all-trans retinoic acid receptor (RAR) and triiodothyronine receptor (TR), which all form functional heterodimers with a common partner, the 9-cis retinoic acid receptor (RXR). The experiment used a cafeteria diet where 60% of the energy was supplied as lipids. This diet was offered to young rats for 8 and 28 days and the expression of nuclear receptors was determined at the end of each experimental time period (1) in the liver by assaying the binding properties of RAR and TR and by quantifying mRNA levels of RAR beta, TR alpha(1)beta(1), RXR alpha, and PPAR alpha, and (2) in the white adipose tissue (WAT) by quantifying mRNA levels of RAR alpha, RXR alpha, TR alpha(1)beta(1), and PPAR gamma(2). After 8 days of cafeteria diet a significant decrease of RAR and TR maximal binding capacity (MBC) was observed in the liver (-20.1% and -35.0%, respectively, P <.05) and the level of the mRNA of RAR beta was significantly decreased (-17.4%, P <.05). After 28 days of cafeteria diet, the level of the mRNA of PPAR alpha and acyl-CoA oxidase (ACOX) was significantly increased (+54.5% and +37.8%, P <.01 and P <.05, respectively), whereas the MBC of RAR and TR was significantly decreased (-16.0% and -23.4%, P <.01), as were the mRNA levels of RAR beta and TR alpha(1) beta(1) (-28.5% and -32.0%, P <.05). The level of RXR alpha mRNA was unchanged. In WAT, the mRNA level of PPAR gamma(2) was significantly increased after 28 days of cafeteria diet (+49.5%, P <.05) and the mRNA levels of RAR alpha and TR alpha(1) beta(1) significantly decreased (-22.3% and -31.0%, P <.05). These results as a whole showed that a high-fat diet can induce early modifications in the pattern of expression of nuclear receptors in the liver and the WAT. These modifications could be compatible with an early adaptive phenomenon. Further investigations are necessary to better understanding the link between the modifications of the pattern of expression of these receptors and plasticity of adipose tissue leading to the onset of obesity.

Effect of a pharmacological activation of PPAR on the expression of RAR and TR in rat liver.

It has recently been shown that high-fat diets induce the expression of peroxisome proliferator-activated receptor (PPAR) with a concomitant decrease in expression of retinoic acid (RAR) and triiodothyronine (TR) receptors in rat liver. The authors have suggested that PPAR activation may be responsible for these modifications in nuclear receptor expression. With the aim of gaining further insight into a possible relationship between the patterns of expression of these receptors, we have examined, using a pharmacological model, the effect of a strong and specific PPAR activation induced by bezafibrate, a peroxisome proliferator agent. Activation of PPAR was evaluated by quantifying PPAR alpha mRNA and acyl-CoA oxidase mRNA. The expression of RAR and TR was determined by assaying the binding properties of these nuclear receptors and by quantifying the mRNA level of RAR beta and TR alpha1,beta1 isoforms. After a 10 day treatment of young rats, induction of PPAR (PPAR alpha mRNA was increased by 40% [P< 0.05 and acyl-CoA oxidase mRNA by 411% [P<0.001]) and a concomitant decrease of RAR and TR expression (Maximal Binding Capacity was decreased by 21 and 26%, respectively [P<0.05]) in the liver was observed. RXR alpha mRNA expression was unchanged by treatment. Cross-talk between RAR, TR and PPAR signalling pathways may be implicated in the new patterns of nuclear receptor expression observed. The decreased expression of RAR and TR reported here could provide a novel element for the understanding of the link between PPAR and tumorigenesis in rat liver.