Henri Garcin

Alterations in carbohydrate and lipid metabolism induced by a diet rich in coconut oil and cholesterol in a rat model

OBJECTIVE The type of dietary fat as well as the amount of cholesterol occurring in the diet have been associated with several metabolic disorders. Thus, the aim of the present study was to investigate the influence of a hypercholesterolemic diet enriched with coconut oil and cholesterol on carbohydrate and lipid metabolism in a rat model. METHODS Twenty male Wistar rats weighing about 190 g were assigned to two dietary groups. One group received a semipurified control diet and the other was given a diet enriched in coconut oil (25% by weight) and cholesterol (1% by weight) for 26 days. RESULTS Our results indicated a significant increase in serum total cholesterol (+285%; p<0.001), low-density lipoproteins (+154%; p<0.01), liver cholesterol (+1509%; p<0.001), as well as a significant increase in liver weight (+46%; p<0.001) in those rats fed the hypercholesterolemia-inducing diet as compared to controls. Moreover, a significant decrease in serum high-density lipoproteins (-67%; p<0.001), triacylglycerols levels (-33%; p<0.05), and abdominal fat weight (-39%; p<0.01) were found. The observed alterations in serum lipid and lipoprotein profile resembled a situation of type IIa hyperlipidemia in humans. Measurement of several enzymes concerned with lipid utilization revealed a significant increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity (+68%; p<0.01) in the liver of animals fed the hypercholesterolemic diet, while a significant reduction in plasma lecithin-cholesterol acyltransferase activity (-66%; p<0.001) was found. The situation of hypoglycemia (-18%; p<0.05) was accompanied by lower levels of serum insulin (-45%; p<0.01) and liver glycogen (-30%; p<0.05) in the hypercholesterolemic rats. Furthermore, glucose utilization was altered since lower glucose-6-Pase (-33%; p<0.05) and increased glucokinase (+212%; p<0.001) activities in the liver were found in the rat model of hypercholesterolemia. CONCLUSION These results provide new evidence that a diet-induced hypercholesterolemia in rats is associated with several adaptative changes in carbohydrate metabolism. These findings may be of importance not only considering the role of western diets on cholesterogenesis, but also in other metabolic disturbances involving lipid and carbohydrate metabolism.

Age-related decreases in mRNA for brain nuclear receptors and target genes are reversed by retinoic acid treatment

Ageing is accompanied by certain problems resulting from changes of hormonal status, in particular thyroid hormone (T3) status and vitamin A status. Since retinoic acid (RA), the active metabolite of vitamin A, and T3 play physiological roles in the adult brain, the effect of ageing on the amounts of mRNA for retinoic acid (RAR and RXR) and triiodothyronine (TR) nuclear receptors were studied. Also, the expression of RA and T3 target genes, tissue transglutaminase (tTG) and neurogranin (RC3), was measured in the whole brain and in the hippocampus of mice. Relative to young (3 months) mice, aged (22 months) mice exhibited lower amounts of RAR, RXR and TR mRNA concomitantly with a lower expression of tTG and RC3. RA administration to old mice (24 h before sacrifice) was able to restore the amount of mRNA of nuclear receptors and of RC3. It is hypothesized that a decrease in the cellular action of RA and T3 could play a role, via a decrease in the expression of RC3, in the alteration of synaptic plasticity occurring in aged mice.

Aging decreases the abundance of retinoic acid (RAR) and triiodothyronine (TR) nuclear receptor mRNA in rat brain: effect of the administration of retinoids

Aging is accompanied by troubles resulting from changes in hormonal and nutritional status. Therefore, the abundance of mRNA coding for triiodothyronine (TR) and retinoic acid (RA) nuclear receptors was studied in the brain of young, adult and aged (2.5, 6 and 24 months, respectively) rats. In the brain of aged rats, there was a lower abundance of TR and RAR mRNA and a lower activity of tissue transglutaminase (tTG), an enzyme the gene of which is a target for retinoids. Administration of RA in these rats restored TR and RAR mRNA and the activity of tTG in the brain. The importance of these observations to the function of the aged brain is discussed.

High-fat diets affect the expression of nuclear retinoic acid receptor in rat liver.

The purpose of this study was to differentiate between the effects of the amount and the type of dietary lipids on the expression of the retinoic acid receptor (RAR), but also the peroxisome proliferator-activated receptor (PPAR) and the receptor of the 9-cis retinoic acid (retinoid X receptor (RXR)) in rat liver. Six groups of eight rats (5-weeks old) were fed during 4 weeks on the following diets: control 50 g vegetable oil/kg, high-fat diet 250 g vegetable oil/kg. These oils were either coconut oil (rich in saturated fatty acids) or olive oil (rich in monounsaturated fatty acids) or safflower oil (rich in polyunsaturated fatty acids, mainly as n-6). The three high-fat diets induced a significant decrease of the maximal binding capacity of RAR and of the abundance of RAR beta mRNA. Simultaneously, an increased expression of PPAR alpha mRNA was observed while no significant difference on abundance of RXR alpha mRNA was observed. The mechanisms involved are probably multiple, but one hypothesis is that a modification of the equilibrium between the nuclear receptors, resulting from an increased expression of PPAR, induces a decreased expression of RAR in rat liver.

Aging decreases retinoic acid and triiodothyronine nuclear expression in rat liver: exogenous retinol and retinoic acid differentially modulate this decreased expression

The expression of nuclear receptors of retinoic acid (RAR) and triiodothyronine (TR) was analyzed in the liver of rats aged 2.5 (young), 6 (adult) and 24 (aged) months. In aged rats, decreased binding properties, binding capacity (Cmax) and affinity (Ka), of nuclear receptors were observed. This resulted, at least in part, from decreased transcription of receptor genes in that the amount of their mRNA also decreased. Moreover, the activity of malic enzyme (ME) and tissue transglutaminase (tTG), whose genes are TR and RAR responsive, respectively, was reduced in aged rats. These results are in agreement with the decreased binding capacity of these receptors. An inducer-related increase of RAR and TR expression was observed 24 h after a single dose of retinoic acid administration (5 mg/kg), while retinol administration (retinyl palmitate, 13 mg/kg) was without incidence on nuclear receptor expression in aged rats.

The influence of dietary vitamin A on triiodothyronine, retinoic acid, and glucocorticoid receptors in liver of hypothyroid rats.

The properties of nuclear receptors belonging to the superfamily of receptors acting as transcription factors are modulated by nutritional and hormonal conditions. We showed recently that retinoic acid (RA) restored to normal the expression of receptors attenuated by hypothyroidism. The present study was designed to find out whether dietary vitamin A (as retinol) had the same effect. Propylthiouracil in drinking water induced both hypothyroidism and a vitamin A-deficient status in rats. The maximum binding capacity (Cmax) of triiodothyronine nuclear receptors (TR) was unchanged, while that of nuclear RA receptors (RAR) and nuclear glucocorticoid hormone receptors (GRn) was reduced in the liver of these hypothyroid rats. The reduced Cmax of RAR stemmed from a lower level of RAR mRNA, while the reduced Cmax of GRn was assumed to be due to reduced translocation of the receptor from the cytosol to the nucleus. Feeding the hypothyroid rats with a vitamin A-rich diet did not restore the Cmax of either RAR or GRn to normal. The lack of effect of dietary retinol on RAR expression may be attributed to either genomic (unoccupied TR block the expression of RAR genes) and/or extragenomic (hypothyroidism decreases the availability of retinol and/or its metabolism to RA) mechanisms. Triiodothyronine is thought to favour the translocation of glucocorticoid hormone receptors from cytosol to nucleus. These findings provide more information on the relationship between vitamin A and hormonal status, showing that a vitamin A-rich diet is without apparent effect on the expression of nuclear receptors in hypothyroid rats.

Retinoids Modulate the Binding Capacity of the Glucocorticoid Receptor and its Translocation from Cytosol to Nucleus in Liver Cells

The binding capacity (Cmax) of the glucocorticoid hormone receptor (GR) was affected by vitamin A status in rat liver. In rats fed on a vitamin A-overloaded diet as well as in rats administered with retinoic acid (RA) there was an increased ratio Cmax of nuclear GR (expressed as fmol/mg liver): Cmax of cytosolic GR (expressed as fmol/mg liver) while in rats fed on a vitamin A-deficient diet this ratio was decreased. These results suggested that an increased amount of RA, resulting from either metabolization of an increased amount of dietary retinol or RA administration, enhanced the translocation of GR from the cytosolic compartment to the nuclear compartment. Moreover such an increased amount of RA could also induce the observed decreased Cmax of the total GR that we observed. These observations were similar to the well known effects of dexamethasone administration on the properties of GR. It is probable that RA, similarly to dexamethasone treatment, induces a dissociation of the tetrameric form of the cytosolic GR and thus enhances translocation of the monomeric form from cytosol to nucleus and also resulting in an increased proteolytic degradation of the receptor.

Chronic ethanol administration enhances retinoic acid and triiodothyronine receptor expression in mouse liver.

Chronic alcoholism induces perturbations of storage and metabolization of retinol and related compounds. After 6 months of ethanol consumption we have observed in mouse liver an increased expression of Tri‐iodothyronine receptors (TR) while the expression of retinoic acid (RA) receptors (RAR) was unaffected. After 10 months of alcoholization the TR expression was strongly increased and the RAR expression was also increased. At this time the activity of aldehyde dehydrogenase and that of alcohol dehydrogenase, two enzymes involved in biosynthesis of RA from retinol, were similar in the liver of alcoholized and pair‐fed mice. Thus it can be hypothesized that (i) the change of RAR expression was, at least in part, the result of a change of TR expression (result in agreement with previous data), (ii) the increased expression of RAR could induce apoptosis and subsequently liver necrosis.

Relative contribution of cysteine and methionine to glutathione content and thyroid hormone levels in the rat.

1. For a period of 24 d rats were given diets containing either casein or pea (Pisum sativum) protein at two different concentrations (180 and 120 g/kg) without or with cysteine or cysteine + methionine supplementation. 2. The effects of these diets on levels of blood and liver reduced glutathione (GSH) and serum thyroid hormones were studied. 3. When compared with the 180 g casein/kg diet, the 120 g casein/kg diet decreased liver GSH and serum thyroid hormone concentrations. These changes were related to dietary cysteine supply since supplementation induced an increase in these variables. 4. When compared with 180 g pea protein/kg diet, the 120 g pea protein/kg diet decreased liver GSH and serum thyroid hormone concentrations. These changes could not be corrected by cysteine or cysteine + methionine supplementation.

Effects of a Large Dose of Retinol or Retinoic Acid on the Thyroid Hormones in the Rat

The daily food intake of a large dose of retinol (as palmitate) or retinoic acid (as all-trans retinoic acid) modifies numerous parameters of the thyroidal status in the rat. There were decreases of the serum total thyroxine (TT4) and triiodothyronine (TT3), and of the biological half-life of T4, while there were increases of the dialyzable fractions of T4 and T3 and of the apparent distribution space of T3. The possible causes of these changes are discussed.