Metabolic syndrome in the rat: females are protected against the pro-oxidant effect of a high sucrose diet

Metabolic syndrome is more prevalent in men than in women. In an experimental dietary model of metabolic syndrome, the high-fructose-fed rat, oxidative stress has been observed in males. Given that estradiol has been documented to exert an antioxidant effect, we investigated whether female rats were better protected than males against the adverse effects of a high-sucrose diet, and we studied the influence of hormonal status in female rats. Males and females were first fed a sucrose-based or starch-based diet for 2 weeks. In the males, the plasma triglyceride (TG)-raising effect of sucrose was accompanied by significantly lowered plasma alpha-tocopherol and a significantly lowered alpha-tocopherol/TG ratio (30%), suggesting that vitamin E depletion may predispose lipoproteins to subsequent oxidative stress. In males, after exposure of heart tissue homogenate to iron-induced lipid peroxidation, thiobarbituric reactive substances were significantly higher in the sucrose-fed than in the starch-fed rats. In contrast, in sucrose-fed females, neither a decrease in vitamin E/TG ratio nor an increased susceptibility of heart tissue to peroxidation was observed, despite both a significantly decreased heart superoxide dismutase activity (14%) and a significant 3-fold increase in plasma nitric oxide concentration compared with starch-fed females. The influence of hormonal status in female rats was then assessed using intact, ovariectomized, or estradiol-supplemented ovariectomized female rats fed the sucrose or starch diet for 2 weeks. After exposure of heart tissue to iron-induced lipid peroxidation, higher susceptibility to peroxidation was found only in ovariectomized females fed the sucrose diet compared with the starch group and not in intact females or ovariectomized females supplemented with estradiol. Thus, estrogens, by their effects on antioxidant capacity, might explain the sexual difference in the pro-oxidant effect of sucrose diet resulting in metabolic syndrome in rats.     

Interacting effects of L-carnitine and malonyl-CoA on rat liver carnitine palmitoyltransferase.

Malonyl-CoA significantly increased the Km for L-carnitine of overt carnitine palmitoyltransferase in liver mitochondria from fed rats. This effect was observed when the molar palmitoyl-CoA/albumin concentration ratio was low (0.125-1.0), but not when it was higher (2.0). In the absence of malonyl-CoA, the Km for L-carnitine increased with increasing palmitoyl-CoA/albumin ratios. Malonyl-CoA did not increase the Km for L-carnitine in liver mitochondria from 24h-starved rats or in heart mitochondria from fed animals. The Km for L-carnitine of the latent form of carnitine palmitoyltransferase was 3-4 times that for the overt form of the enzyme. At low ratios of palmitoyl-CoA/albumin (0.5), the concentration of malonyl-CoA causing a 50% inhibition of overt carnitine palmitoyltransferase activity was decreased by 30% when assays with liver mitochondria from fed rats were performed at 100 microM-instead of 400 microM-carnitine. Such a decrease was not observed with liver mitochondria from starved animals. L-Carnitine displaced [14C]malonyl-CoA from liver mitochondrial binding sites. D-Carnitine was without effect. L-Carnitine did not displace [14C]malonyl-CoA from heart mitochondria. It is concluded that, under appropriate conditions, malonyl-CoA may decrease the effectiveness of L-carnitine as a substrate for the enzyme and that L-carnitine may decrease the effectiveness of malonyl-CoA to regulate the enzyme.     

Comparative effects of dietary fat types on hepatic enzyme activities related to the synthesis and oxidation of fatty acid and to lipogenesis in rats

The effects of different types of dietary fat on the activities of hepatic enzymes related to fatty acid synthesis [glucose-6-phosphate dehydrogenase (G6PDH) and acetyl-CoA carboxylase (ACC)], oxidation [acyl-CoA synthetase (AST), carnitine palmitoyl transferase (CPT), and peroxisomal beta-oxidation (PbetaOX)], and lipogenesis [phosphatidate phosphohydrolase (PAP), diacylglycerol acyltransferase (DGAT), and phosphocholine diacylglycerol transferase (PCDGT)], and plasma and liver lipid levels were investigated in male Wistar rats. The animals were 6 weeks old and about 120 g of body weight, and were fed on test diets containing 20% of a mixture of tripalmitin, tristearin and corn oil (SFA), olive oil (OLI), sunflower oil (SUN), linseed oil (LIS), and sardine oil (SAR) for 2 weeks. The concentrations of plasma total cholesterol (T-CHOL), high-density lipoprotein-cholesterol (HDL-CHOL), triacylglycerol (TG) and phospholipid (PL) were generally higher in the rats fed on SFA and OLI than in those given SUN, LIS and SAR. The rats fed on OLI had a higher level of liver T-CHOL than those fed on the other fats. The liver TG content was nearly higher from the intake of SFA and OLI than from SUN, LIS and SAR, although the liver PL level was not affected by the type of dietary fat. The SFA and OLI groups had the highest activities of hepatic G6PDH and ACC, and the SAR group, the lowest activities. The activities of AST and CPT, and peroxisomal PbetaOX in the liver were higher in the rats fed on the LIS and SAR diets than in those given the other diets. The hepatic PAP activity was higher from the intake of OLI and SUN, and tended to be higher from SFA than from LIS and SAR. The activity of liver DGAT was higher from SFA and inclined to be higher from OLI, SUN, and LIS than from SAR, while the PCDGT activity in the liver was not effected by the type of dietary fat. The concentrations of plasma and liver TG were generally positively correlated with the activities of liver enzymes related to the synthesis of fatty acids and lipids, and negatively with those involved in fatty acid oxidation. Based on these results, it is suggested that the levels of plasma and liver TG were controlled by different types of dietary fat through changes in the hepatic enzyme activities related to fatty acid synthesis, lipogenesis, and fatty acid oxidation.     

Comparative Effects of Dietary Fat Types on Hepatic Enzyme Activities Related to the Synthesis and Oxidation of Fatty Acid and to Lipogenesis in Rats

The effects of different types of dietary fat on the activities of hepatic enzymes related to fatty acid synthesis {glucose-6-phosphate dehydrogenase (G6PDH) and acetyl-CoA carboxylase ACC)}, oxidation {acyl-CoA synthetase (AST), carnitine palmitoyl transferase (CPT), and peroxisomal β-oxidation (P βOX)}, and lipogenesis {phosphatidate phosphohydrolase (PAP), diacylglycerol acyltransferase (DGAT), and phosphocholine diacylglycerol transferase (PCDGT)}, and plasma and liver lipid levels were investigated in male Wistar rats. The animals were 6 weeks old and about 120 g of body weight, and were fed on test diets containing 20% of a mixture of tripalmitin, tristearin and corn oil (SFA), olive oil (OLI), sunflower oil (SUN), linseed oil (LIS), and sardine oil (SAR) for 2 weeks. The concentrations of plasma total cholesterol (T-CHOL), high-density lipoprotein-cholesterol (HDL-CHOL), triacylglycerol (TG) and phospholipid (PL) were generally higher in the rats fed on SEA and OLI than in those given SUN, LIS and SAR. The rats fed on OLI had a higher level of liver T-CHOL than those fed on the other fats. The liver TG content was nearly higher from the intake of SFA and OLI than from SUN, LIS and SAR, although the liver PL level was not affected by the type of dietary fat. The SFA and OLI groups had the highest activities of hepatic G6PDH and ACC, and the SAR group, the lowest activities. The activities of AST and CPT, and peroxisomal P βOX in the liver were higher in the rats fed on the LIS and SAR diets than in those given the other diets. The hepatic PAP activity was higher from the intake of OLI and SUN, and tended to be higher from SFA than from LIS and SAR. The activity of liver DGAT was higher from SFA and inclined to be higher from OLI, SUN, and LIS than from SAR, while the PCDGT activity in the liver was not effected by the type of dietary fat. The concentrations of plasma and liver TG were generally positively correlated with the activities of liver enzymes related to the synthesis of fatty acids and lipids, and negatively with those involved in fatty acid oxidation. Based on these results, it is suggested that the levels of plasma and liver TG were controlled by different types of dietary fat through changes in the hepatic enzyme activities related to fatty acid synthesis, lipogenesis, and fatty acid oxidation.     

Effect of L-Carnitine Supplementation on Utilisation of Energy and Protein in Broiler Chicken Fed Different Dietary Fat Levels

Effects of a supplementation of 80mg L-carnitine perkg diet were studied in broiler chicken at two dietary levels of fat (4 and 8 %) and different feeding levels (ad libitum in a growth trial, 95 and 85 % of ad libitum in a balance trial). A low-carnitine basal diet adequate in amino acid concentration was used. In the growth trial, each diet was fed to 9 groups of 10 birds each for 16 days from day 5 of live onwards. Growth and feed intake were determined. At the end of the trial, birds were killed and homogenised for subsequent empty body analysis. Accretion of protein and energy was determined using a representative blank group killed at the beginning of the trial. In the balance trial, 8 individual birds were used per treatment. Birds were offered the feed at approximately 85 and 95% of ad libitum intake, which was determined with separate birds for both fat levels. Excreta were quantitatively collected three times daily for 8 consecutive days beginning on day 17 individually for each bird. Supplemented L-carnitine did not significantly affect any response criterion. However, growth and feed conversion tended to be improved by about 5% in the carnitine supplemented diets when fed ad libitum. An interaction between carnitine and fat level occurred with regard to feed conversion, indicating that carnitine had a positive effect at the high fat level, but not at the low fat level. L-carnitine did not positively affect the metabolisability of energy (ME/GE) and the efficiency of energy utilisation (RE/GE or RE/ME). Similarly, no significant carnitine effect was determined with regard to N accretion and the efficiency of utilisation of dietary protein in both trials. It is concluded that endogenous carnitine synthesis is not the limiting factor for energy utilisation in broiler chicken, even at high dietary fat concentration. Occasionally reported positive effects of supplemental carnitine were likewise caused by reasons other than improved energy or protein utilisation. Further studies on amino acid utilisation and catabolism should consider marginal amino acid supply.     

Effects of l-carnitine and niacin supplied by drinking water on fattening performance,carcass quality and plasma l-carnitine concentration of broiler chicks

The present study was initiated to determine whether dietary supplemental L-carnitine and niacin affect growth performance, carcass yield, abdominal fat and plasma L-carnitine concentration of broiler chicks. One-day-old broiler chicks (COB500) were used in the experiment. A two by two factorial arrangement was employed with two levels (0 and 50 mg/l) of supplemental L-carnitine and two levels (0 or 50 mg/l) of supplemental niacin in drinking water as main effects. Body weight gain was significantly improved by L-carnitine, or L-carnitine + niacin supplementation during the first 3 weeks. However, supplemental L-carnitine and niacin did not change body weight gain during the last 3 weeks of the experimental period. Supplemental L-carnitine significantly improved feed intake during the first 3 weeks. Supplemental L-carnitine or niacin did not influence carcass weight, carcass yield and abdominal fat weight. L-carnitine content in the plasma was significantly higher in the groups receiving supplemental L-carnitine and L-carnitine + niacin. It is concluded that dietary supplemental L-carnitine or L-carnitine + niacin could have positive effects on body weight gain and feed intake during the early stages of growing. However, supplemental L-carnitine or L-carnitine + niacin were not of benefit regarding the complete growth period.     

Tissue specific depletion of L-carnitine in rat heart and skeletal muscle by D-carnitine

L-carnitine deficiency in heart and skeletal muscle was induced by intraperitoneal injection of D-carnitine into starved or fed rats. Carnitine levels in kidney were slightly lowered, but liver, brain and plasma were unaffected. L-carnitine deficient hearts were unable to maintain normal cardiac function when perfused in an isolated working heart apparatus with palmitate as the only perfused substrate. These findings indicate that tissue levels of carnitine in heart and skeletal muscle are maintained $\text{in vivo}$ by an exchange transport mechanism. It is postulated that the depletion of L-carnitine from these tissues occurs by an exchange of the D- and L-isomer across the cell membrane. The technique may be useful for estimating the levels of carnitine required for fatty acid oxidation and normal cardiac and skeletal muscle function; however, interpretation of such tests may be complicated by the inhibitory effects of the D-isomer upon carnitine transferase enzymes.     

Effect of low dietary rubidium on plasma biochemical parameters and mineral levels in rats

The effects of low dietary rubidium on plasma biochemical parameters and mineral levels in tissues in rats were studied. Eighteen male Wistar rats, weighing about 40 g, were divided into two groups and fed the diets with or without supplemental rubidium (0.54 vs 8.12 mg/kg diet) for 11 wk. Compared to the rats fed the diet with supplemental rubidium, the animals fed the diet without rubidium supplementation had higher urea nitrogen in plasma; lower rubidium concentration in tissues; lower sodium in muscle; higher potassium in plasma, kidney and tibia, and lower potassium in testis; lower phosphorus in heart and spleen; lower calcium in spleen; higher magnesium in muscle and tibia; higher iron in muscle; lower zinc in plasma and testis; and lower copper in heart, liver, and spleen, and higher copper in kidney. These results suggest that rubidium concentration in tissues reflects rubidium intake, and that rubidium depletion affects mineral (sodium, potassium, phosphorus, calcium, magnesium, iron, zinc, and copper) status.     

EFFECTS OF DIETARY SUPPLEMENTAL L-CARNITINE AND ASCORBIC ACID ON PERFORMANCE,CARCASS COMPOSITION AND PLASMA L-CARNITINE CONCENTRATION OF BROILER CHICKS REARED UNDER DIFFERENT TEMPERATURE

The present study was initiated to determine whether dietary supplemental L-carnitine and ascorbic acid affect growth performance, carcass yield and composition, abdominal fat and plasma L-carnitine concentration of broiler chicks reared under normal and high temperature. During the experiment, two temperature regimes were employed in two experimental rooms, which were identical but different in environmental temperature. The regimes were thermoneutral (20-22°C for 24 h) or recycling hot (34-36°C for 8 h and 20-22°C for 16 h). One-day-old broiler chicks (ROSS) were used in the experiment. A 2 x 2 x 2 factorial arrangement was employed with two levels (0 and 50 mg/kg) of supplemental L-carnitine and two levels (0 or 500 mg/kg) of supplemental ascorbic acid in drinking water under thermoneutral or high temperature regimes. Body weight gain was affected by high temperature. However, body weight gain was significantly improved in animals receiving supplemental L-carnitine, ascorbic acid or L-carnitine + ascorbic acid compared to animals receiving unsupplemented diet under high temperature. On the other hand, supplemental L-carnitine or L-carnitine + ascorbic acid reduced body weight gain under thermoneutral condition. Supplemental ascorbic acid significantly improved feed conversion efficiency, the improvement was relatively greater under high temperature. The L-carnitine content in the plasma was higher in the groups receiving supplemental L-carnitine and ascorbic acid under high temperature, while broilers fed supplemental L-carnitine and ascorbic acid had a decreased level of plasma L-carnitine concentration under normal temperature. It is concluded that dietary supplemental L-carnitine or L-carnitine + ascorbic acid may have positive effects on body weight gain, carcass weight under high temperature conditions.     

Surplus acylcarnitines in the plasma of starved rats derive from the liver

The method used here to assess the contribution of liver to plasma acylcarnitine is based on the idea that in rat, shortly after administration of [3H]butyrobetaine the [3H]carnitine appearing in the plasma derives from the liver and so does the acyl moiety of [acyl-3H] carnitine. In the perchloric acid extracts of plasma and liver, the ester fraction of total carnitine was determined by enzymatic analysis and that of [3H]carnitines was determined by high performance liquid chromatography. The ester fraction of total carnitine in the plasma of fed rats was 32.6% while that of [3H]carnitines was 67.9%, 1 h following injection of [3H]butyrobetaine. For 48 h starved rats the equivalent values were 54.2 and 84.0%, respectively. 24 h after the administration of [3H]butyrobetaine, the ester content became the same in the total and [3H]carnitines. That the newly synthesized carnitine was more acylated (67.9 versus 32.6%, fed) indicates that liver exports acyl groups with carnitine as carrier. The observation that the ester fraction in the newly synthesized plasma carnitine increased with fasting (84.0 versus 67.9%) indicates that the surplus plasma acylcarnitine in fasting ketosis derives from the liver. Perfused livers, however, released carnitine with the same ester content (60-61%) whether they were from fed or fasted animals. Probably, the increased plasma [acylcarnitine] in fasting develops not by an increased ester output from the liver but by an altered handling in extrahepatic tissues.     

Elevated body fat in rats by the dietary nitric oxide synthase inhibitor, L-N omega nitroarginine.

The influence of the dietary nitric oxide (NO) synthase inhibitor, L-N omega nitroarginine (L-NNA) on body fat was examined in rats. In experiment 1, all rats were fed with the same amount of diet with or without 0.02% L-NNA for 8 wk. L-NNA intake caused elevations in serum triglyceride and body fat, and reduction in serum nitrate (a metabolite of nitric oxide). The activity of hepatic carnitine palmitoyltransferase was reduced by L-NNA. In experiment 2, rats were fed for 8 wk with the same amount of diets with or without 0.02% L-NNA supplemented or not with 4% L-arginine. The elevation in body fat, and the reductions in serum nitrate and in the activity of hepatic carnitine palmitoyltransferase by L-NNA were all suppressed by supplemental L-arginine. The results suggest that lower NO generation elevated not only serum triglyceride, but also body fat by reduced fatty acid oxidation.     

The effect of exogenous L-carnitine on fat diet-induced hyperlipidemia in the rat

In rats receiving a fat diet (75% Altromin R and 25% olive oil) ad libitum for 15 hours, an orally administered dose of 500 mg/kg L-carnitine produces: an increase in serum carnitine and acetyl-carnitine levels; a decrease in serum triglyceride (TG) and free fatty acid (FFA) levels; a normalization of the heart and liver carnitine pattern; a reduction of myocardial neutral lipase (NL) activity, without affecting lipoprotein lipase (LPL) of the heart. Under these experimentally-induced conditions, L-carnitine stimulates the excretion of acyl groups as acyl-carnitines with the urine. Acylcarnitines are practically absent from the urine of control animals.     

Short-term administration of conjugated linoleic acid reduces liver triglyceride concentration and phosphatidate phosphohydrolase activity in OLETF rats

The present study explored the short-term effects of dietary conjugated-linoleic acid (CLA) on liver lipid metabolism in starved/refed Otsuka Long Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (12 weeks old) were starved for 24 hours, then refed for 48 hours with either a CLA diet [7.5% CLA and 7.5% Safflower oil (SAF)] or a SAF control diet (15% SAF). The results demonstrated a 30% reduction of hepatic triglyceride (TG) concentration in the CLA group when compared to the control group. Liver cholesterol concentration was also 26% lower in the CLA fed rats. The activity of mitochondrial carnitine palmitoyltransferase, the rate-limiting enzyme of fatty acid oxidation, was moderately elevated by 1.2-fold in the livers of the CLA group when compared to the control. In contrast, phosphatidate phosphohydrolase, the rate-limiting enzyme for TG synthesis, was found to be 20% lower in the livers of the CLA-fed rats. Therefore, dietary CLA evidently lowers liver lipid concentrations through a reduced TG synthesis and enhanced fatty acid oxidation in starved/refed OLETF rats.     

高淀粉膳食对血浆胰岛素、cAMP含量及组织cAMP代谢的影响

对高淀粉膳食(糖占总热量80％)对大鼠血脂、胰岛素及cAMP代谢的影响进行了研究。大鼠摄取高淀粉膳食3天,空腹血浆岛素及甘油三酯含量明显高于对照组(P<0.01;P<0.01)。6天后血浆甘油三酯含量增高近四倍(P<0.01),而血浆、肌肉和脂肪组织cAMP含量低于对照组,分别减低38％,45％和32％(P<0.05;P<0.05,0.1相似文献   

Suppression of hepatic prostaglandin F2 alpha in rats by dietary alpha-tocopherol acetate is independent of total hepatic alpha-tocopherol.

Groups of eight weanling female F344/N rats were fed semipurified diets that supplied 0, 50, 500, 5000, or 15,000 mg alpha-tocopherol acetate/kg diet, with and without 0.05% phenobarbital (PB) for 9 weeks. Both plasma and hepatic alpha-tocopherol levels, measured by HPLC, strongly correlated with alpha-tocopherol intake (r greater than 0.73, p less than 0.0001). Phenobarbital both depleted hepatic alpha-tocopherol and increased plasma alpha-tocopherol significantly. Although treatment with PB for 9 weeks significantly increased GST activity, PB did not affect hepatic prostaglandin (PG)F2 alpha status, as determined by radioimmunoassay. PGF2 alpha was significantly greater (by 52%) in rats fed no alpha-tocopherol than in rats fed 15,000 mg alpha-tocopherol acetate/kg diet. Hepatic PGF2 alpha status was correlated inversely but weakly with dietary alpha-tocopherol (r = -0.24, p less than 0.05). Hepatic PGF2 alpha status was not correlated with hepatic or plasma alpha-tocopherol status. This finding suggests either that there is a small depletion-resistant subcellular alpha-tocopherol pool which regulates PGF2 alpha production or that alpha-tocopherol alters PGF2 alpha production in vivo by an indirect mechanism.     

Inverse modifications of heart and liver alpha-tocopherol status by various dietary n-6/n-3 polyunsaturated fatty acid ratios

The effect of dietary n-6/n-3 fatty acid ratio on alpha-tocopherol homeostasis was investigated in rats. Animals were fed diets containing fat (17% w/w) in which the n-6/n-3 ratio varied from 50 to 0.8. This was achieved by combining corn oil, fish oil, and lard. The polyunsaturated to saturated ratio and total alpha-tocopherol remained constant in all diets. Results showed that enrichment of n-3 polyunsaturated fatty acids in the diet, even at a low amount (3.9% w/w), resulted in a dramatic reduction of blood alpha-tocopherol concentration, which, in fact, is the result of a decrease in plasma lipids, since the alpha-tocopherol to total lipids ratio was not significantly altered. The most striking effect observed was a considerable alpha-tocopherol enrichment (x 4) of the heart as its membranes became enriched with n-3 polyunsaturated fatty acids. This process appeared even with a low amount of fish oil (3.9% w/w) added to the diet. Accordingly, a strong positive correlation was found between heart alpha-tocopherol and docosahexaenoic acid (r = 0.86) or docosahexaenoic acid plus eicosapentaenoic acid levels (r = 0.84). Conversely, the liver alpha-tocopherol level dropped dramatically when n-3 polyunsaturated fatty acids were gradually added to the diet. It is concluded that fish oil intake dramatically alters the alpha-tocopherol homeostasis in rats.     

Ester composition of carnitine in the perfusate of liver and in the plasma of donor rats

When the carnitine pool of fed rats was labelled with tritium, in non-recirculating perfusate of their liver 44% of acid-soluble 3H activity was identified as free carnitine and 47% as short-chain acylcarnitine. Of the latter component acetylcarnitine accounted for 30% and propionylcarnitine for 10% of total acid-soluble. In plasma the contribution of short-chain acylcarnitines to total carnitine in fed, fasted and diabetic rats was 15.6%, 43.1% and 48.0%, respectively. Recirculating perfusion of livers from the same animals revealed that livers from fed rats released short-chain acylcarnitines as much as 56.2% of total and this proportion did not increase further in the other two groups. At the same time, ketone bodies in the perfusate increased gradually in the fed, fasted and diabetic group, paralleling the plasma ketone levels. Although liver supplies the organism with carnitine the increment of plasma short-chain acylcarnitines seen in ketosis is not a result of some extra output by the liver.     

Age-associated decreased activities of mitochondrial electron transport chain complexes in heart and skeletal muscle: role of L-carnitine

The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and aging. L-Carnitine (4-N-trimethylammonium-3-hydroxybutric acid) plays an important role in transport of fatty acid from cytoplasm to mitochondria for energy production. Previous studies in our laboratory reported L-carnitine as a free radical scavenger in aged rats. In the present study we focused the effect of L-carnitine on the activities of electron transport chain in young and aged rats. The activities of electron transport chain complexes were found to be significantly decreased in aged rats when compared to young control rats. Supplementation of carnitine to young and aged rats for 14 and 21 days improved the electron transport chain complexes levels in aged rats when compared with young rats in duration dependent manner. No significant changes were observed in young rats. Our result suggested that L-carnitine improved the activities of electron transport chain enzymes there by improving the energy status in aged rats.     

Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation

Aims

Trimethylamine-N-oxide (TMAO) is produced in host liver from trimethylamine (TMA). TMAO and TMA share common dietary quaternary amine precursors, carnitine and choline, which are metabolized by the intestinal microbiota. TMAO recently has been linked to the pathogenesis of atherosclerosis and severity of cardiovascular diseases. We examined the effects of anti-atherosclerotic compound meldonium, an aza-analogue of carnitine bioprecursor gamma-butyrobetaine (GBB), on the availability of TMA and TMAO.

Main methods

Wistar rats received L-carnitine, GBB or choline alone or in combination with meldonium. Plasma, urine and rat small intestine perfusate samples were assayed for L-carnitine, GBB, choline and TMAO using UPLC-MS/MS. Meldonium effects on TMA production by intestinal bacteria from L-carnitine and choline were tested.

Key findings

Treatment with meldonium significantly decreased intestinal microbiota-dependent production of TMA/TMAO from L-carnitine, but not from choline. 24 hours after the administration of meldonium, the urinary excretion of TMAO was 3.6 times lower in the combination group than in the L-carnitine-alone group. In addition, the administration of meldonium together with L-carnitine significantly increased GBB concentration in blood plasma and in isolated rat small intestine perfusate. Meldonium did not influence bacterial growth and bacterial uptake of L-carnitine, but TMA production by the intestinal microbiota bacteria K. pneumoniae was significantly decreased.

Significance

We have shown for the first time that TMA/TMAO production from quaternary amines could be decreased by targeting bacterial TMA-production. In addition, the production of pro-atherogenic TMAO can be suppressed by shifting the microbial degradation pattern of supplemental/dietary quaternary amines.     

Content of liver and brain ubiquinol-9 and ubiquinol-10 after chronic ethanol intake in rats subjected to two levels of dietary alpha-tocopherol

To assess the effect of chronic ethanol ingestion in the content of the reduced forms of coenzymes Q9 (ubiquinol-9) and Q10 (ubiquinol-10) as a factor contributing to oxidative stress in liver and brain, male Wistar rats were fed ad libitum a basal diet containing either 10 or 2.5 mg alpha-tocopherol/100 g diet (controls), or the same basal diet plus a 32% ethanol-25% sucrose solution. After three months treatment, ethanol chronically-treated rats showed identical growth rates to the isocalorically pair-fed controls, irrespectively of alpha-tocopherol dietary level. Lowering dietary alpha-tocopherol led to a decreased content of this vitamin in the liver and brain of control rats, without changes in that of ubiquinol-9, and increased levels of hepatic ubiquinol-10 and total glutathione (tGSH), accompanied by a decrease in brain tGSH. At the two levels of dietary alpha-tocopherol, ethanol treatment significantly decreased the content of hepatic alpha-tocopherol and ubiquinols 9 and 10. This effect was significantly greater at 10 mg alpha-tocopherol/100 g diet than at 2.5, whereas those of tGSH were significantly elevated by 43% and 9%, respectively. Chronic ethanol intake did not alter the content of brain alpha-tocopherol and tGSH, whereas those of ubiquinol-9 were significantly lowered by 20% and 14% in rats subjected to 10 and 2.5 mg alpha-tocopherol/100 g diet, respectively. It is concluded that chronic ethanol intake at two levels of dietary alpha-tocopherol induces a depletion of hepatic alpha-tocopherol and ubiquinols 9 and 10, thus contributing to ethanol-induced oxidative stress in the liver tissue. This effect of ethanol is dependent upon the dietary level of alpha-tocopherol, involves a compensatory enhancement in hepatic tGSH availability, and is not observed in the brain tissue, probably due to its limited capacity for ethanol biotransformation and glutathione synthesis.