Nuclear receptors and hepatic lipidogenic enzyme response to a dyslipidemic sucrose-rich diet and its reversal by fish oil n-3 polyunsaturated fatty acids.

A sucrose-rich diet (SRD), compared with a starch diet, induces time-dependent metabolic disorders and insulin resistance with hypertriglyceridemia, similar to type 2 diabetes. In this study, we examined the effect of SRD, after 8 mo, on nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha), and liver X receptor-alpha (LXRalpha), stearoyl-CoA desaturase-1 (SCD-1), and Delta6 and Delta5 desaturases mRNA and activity, hepatic enzymes involved in lipid metabolism, and fatty acid (FA) composition as well as the reversal produced by cod liver oil. SRD induced triglyceride increase in plasma and liver, increasing the anabolic FA synthase, malic enzyme, and glucose-6-phosphate dehydrogenase, but not the prooxidative enzymes FA oxidase and carnitine palmitoyltransferase I, and correspondingly decreased PPARalpha and increased LXRalpha expressions. Results suggest a contribution of both nuclear receptors' interaction on these enzymatic activities. SRD depressed SCD-1 without altering oleic acid proportion and increased Delta6 and Delta5 desaturases and the proportion of n-6 arachidonic acid. Therefore, the data do not support that SRD hypertriglyceridemia is produced by increased SCD-1-dependent oleic acid biosynthesis. The administration of 7% cod liver oil for 2 mo depressed LXRalpha, enhancing PPARalpha in control and SRD-fed rats, reversing the activity of the hepatic enzymes involved in lipid metabolism and therefore the hyperlipidemia produced by the SRD. Fish oil increased n-3 PUFA and depressed n-6 PUFA of liver lipids without altering the 18:1/18:0 ratio, suggesting that its effects were produced mainly by competition of dietary n-6 and n-3 FA and not through desaturase activity modification.

Role of liver X receptor, insulin and peroxisome proliferator activated receptor alpha on in vivo desaturase modulation of unsaturated fatty acid biosynthesis.

We examined the in vivo contribution of insulin, T090137 (T09), agonist of liver X receptor (LXR), fenofibrate, agonist of peroxisome proliferator activated receptor (PPAR-alpha) and sterol regulatory element binding protein-1c (SREBP-1c) on the unsaturated fatty acid synthesis controlled by Delta6 and Delta5 desaturases, compared with the effects on stearoylcoenzyme A desaturase-1. When possible they were checked at three levels: messenger RNA (mRNA), desaturase protein and enzymatic activity. In control rats, only fenofibrate increased the insulinemia that was maintained by the simultaneous administration of T09, but this increase has no specific effect on desaturase activity. T09 enhanced SREBP-1 in control animals and the mRNAs and activity of the three desaturases in control and type-1 diabetic rats, demonstrating a LXR/SREBP-1-mediated activation independent of insulin. However, simultaneous administration of insulin and T09 to diabetic rats led to a several-fold increase of the mRNAs of the desaturases, suggesting a strong synergic effect between insulin and LXR/retinoic X receptor (RXR). Moreover, this demonstrates the existence of an interaction between unsaturated fatty acids and cholesterol metabolism performed by the insulin/SREBP-1c system and LXR/RXR. PPAR-alpha also increased the expression and activity of the three desaturases independently of the insulinemia since it was equivalently evoked in streptozotocin diabetic rats. Besides, PPAR-alpha increased the palmitoylcoenzyme A elongase, evidencing a dual regulation in the fatty acid biosynthesis at the level of desaturases and elongases. The simultaneous administration of fenofibrate and T09 did not show additive effects on the mRNA expression and activity of the desaturases. Therefore, the results indicate a necessary sophisticated interaction of all these factors to produce the physiological effects.

Effects of fenofibrate and insulin on the biosynthesis of unsaturated fatty acids in streptozotocin diabetic rats.

Both insulin and PPAR-alpha up-modulate hepatic Delta9, Delta6 and Delta5 desaturating enzymes involved in the biosynthesis of mono- and polyunsaturated fatty acids. Currently, we have examined for 9 days the independent and simultaneous effects of daily glargine insulin and fenofibrate administration on the insulinemia, glycemia, hepatic acyl-CoA oxidase activity and mRNAs and enzymatic activities of stearoyl-CoA desaturase-1 (SCD-1) and Delta5 desaturase in streptozotocin diabetic rats. Glargine insulin depressed the hyperglycemia of diabetic rats at 4h, but not after 24h of injection. Fenofibrate increased the radioimmunoreactive insulinemia in non-diabetic rats without changing the glycemia. Insulin increased the mRNAs and activities of SCD-1 and Delta5 desaturase depressed in diabetic rats. Fenofibrate increased acyl-CoA oxidase activity, and the mRNAs and activities of both desaturating enzymes in non-diabetic, diabetic and insulin-treated diabetic rats, but was less effective in the mRNAs modification of diabetic animals. Therefore, insulin, and fenofibrate through PPAR-alpha activation, enhance liver mRNAs and activities of SCD-1 and Delta5 desaturases independently and synergistically through different mechanisms. Insulin and fenofibrate independently increased the 18:1/18:0 ratio in liver lipids, increasing the fluidity of the membranes. The 20:4/18:2 ratio was maintained. Fenofibrate increased palmitic acid, but decreased stearic acid percentage in liver lipids.

Desaturase activities in rat model of insulin resistance induced by a sucrose-rich diet.

A sucrose-rich diet, as compared with a similar starch diet, induces a time-dependent typical noninsulin-dependent diabetes syndrome characterized by insulin resistance in rats. Within the first 3 wk, there was glucose intolerance associated with hyperinsulinemia, hypertriglyceridemia, and high plasma FFA. In this study, we examined the effect of the sucrose-rich diet vs. the starch diet during short- (3 wk) and longterm treatment (6 mon) on hepatic delta9, delta6, and delta5 desaturases. These enzymes modulate monounsaturated FA and PUFA biosynthesis, respectively. Sucrose feeding (3 wk) caused an initial hyperinsulinemia that was normalized within 6 mon. In the early period (3 wk), stearoyl-CoA desaturase-1 (SCD-1) mRNA and activity were decreased, whereas delta6 desaturase mRNA abundance and delta6 and delta5 desaturase activities remained unchanged. After 6 mon of sucrose feeding, activities of the delta9, delta6, and delta5 desaturases were each increased. The SCD-1 and delta6 desaturase mRNA were also correspondingly higher. These increases were consistent with an increase in oleic acid, the 20:4/18:2 ratio, and 22:4n-6 and 22:5n-6 acids in liver and muscle lipids. On the other hand, the percentage of 22:6n-3 acid was decreased. In conclusion, a sucrose-rich diet after 6 mon induces an increase in rat liver SCD-1 and delta6 desaturase mRNA and enzymatic activities that are opposite to the changes reported in insulin-dependent diabetes mellitus. It appears that neither blood insulin levels nor insulin resistance is a factor affecting the delta9, delta6, and delta5 desaturase changes in mRNA and activity found with the sucrose-rich diet.

Dietary cholesterol modulates delta6 and delta9 desaturase mRNAs and enzymatic activity in rats fed a low-eFA diet.

The effects of a 1% addition of cholesterol to a diet low in EFA on FA desaturases were examined. The administration of cholesterol markedly increased the esterified cholesterol content in microsomes and total liver lipids from the first day, whereas the proportion of free cholesterol remained unaltered throughout the treatment. An excellent homeostasis in the free cholesterol content was apparently evoked by the acyl-CoA cholesterol acyltransferase. The cholesterol esters were mainly oleate, palmitate, and stearate, and the addition of cholesterol increased the relative proportions of cholesterol palmitoleate and oleate. The addition of cholesterol to a low-EFA diet induced, as in animals fed a high-EFA diet, a marked increase in liver stearoyl-CoA desaturase-1 mRNA and enzyme activity. This increased activity apparently evoked a similar enhancement of palmitoleic and oleic acids in total and microsomal liver lipids. The cholesterol-rich diet depressed the liver A6 and delta5 desaturase activity. However, the abundance of delta6 desaturase mRNA was not modified throughout the treatment. This indicates that the depressive effect is evoked at a step beyond that controlled by the mRNA level. The depression of both enzymatic activities was consistent with the decrease in the percentages of arachidonic acid and DHA in total and microsomal liver lipids. Taken together, these results indicate that through its modulating effect on the desaturases, dietary cholesterol may lead an animal or human fed low-EFA diet to a true deficiency by the decreased synthesis of the highly polyunsaturated acids derived from linoleic and alpha-linolenic acids.

Aporte de acidos grasos esenciales de las series n-6 y n-3 a la dieta humana por pescados comestibles del rio Parana / Essential fatty acids on n-6 and n-3 series supplied to human diet by edible fish from the Paraná river

Se estudió la composición de los ácidos grasos de los lípidos musculares de los pescados comestibles del río Paraná: Dorado (Salminus maxillosus), Boga (Leporinus Affinis), Patí (Luciopimelodus pati) y Surubí (Pseudoplatistoma coruscans) con el fin de conocer su valor alimenticio en cuanto al aporte de ácidos grasos esenciales de las series n-6 y n-3. Las carnes de estos pescados son relativamente magras y sus lípidos contienen sólo entre 35 por ciento y 38 por ciento de ácidos grasos saturados. Todos los pescados estudiados tienen cantidades substanciales de ácidos polietilénicos n-6, principalmente linoleico y araquidónico y de ácidos n-3, principalmente los ácidos docosahexenoico, docosapentenoico, eicosapentenoico y alpha-linolénico. La carne de Patí es la que más ácidos n-6 aporta a la dieta con un valor índice de 306 mg por 100 g de músculo y le siguen Boga, Dorado y Surubí. La mayor proporción de ácidos n-3 es aportada por los músculos de Dorado con 183 mg por 100 g de músculo y le siguen Patí, Boga y Surubí. Más del 90 por ciento de los lípidos que aportan estos ácidos son triacilgliceroles para el Dorado, Boga y Patí. En el caso del Surubí, del orden del 60 por ciento son triacilgliceroles y el resto fosfolípidos. El contenido de colesterol de la carne de los pescados de agua dulce analizados no pasa de 4,7 mug por gramo de músculo para el Patí y es menor para los otros ejemplares estudiados. Los pescados considerados resultan ser una buena fuente de ácidos grasos polinosaturados tanto n-6 como n-3 para la dieta de la población mediterránea del país.

Aporte de acidos grasos esenciales de las series n-6 y n-3 a la dieta humana por pescados comestibles del rio Parana / Essential fatty acids on n-6 and n-3 series supplied to human diet by edible fish from the Paraná river

Se estudió la composición de los ácidos grasos de los lípidos musculares de los pescados comestibles del río Paraná: Dorado (Salminus maxillosus), Boga (Leporinus Affinis), Patí (Luciopimelodus pati) y Surubí (Pseudoplatistoma coruscans) con el fin de conocer su valor alimenticio en cuanto al aporte de ácidos grasos esenciales de las series n-6 y n-3. Las carnes de estos pescados son relativamente magras y sus lípidos contienen sólo entre 35 por ciento y 38 por ciento de ácidos grasos saturados. Todos los pescados estudiados tienen cantidades substanciales de ácidos polietilénicos n-6, principalmente linoleico y araquidónico y de ácidos n-3, principalmente los ácidos docosahexenoico, docosapentenoico, eicosapentenoico y alpha-linolénico. La carne de Patí es la que más ácidos n-6 aporta a la dieta con un valor índice de 306 mg por 100 g de músculo y le siguen Boga, Dorado y Surubí. La mayor proporción de ácidos n-3 es aportada por los músculos de Dorado con 183 mg por 100 g de músculo y le siguen Patí, Boga y Surubí. Más del 90 por ciento de los lípidos que aportan estos ácidos son triacilgliceroles para el Dorado, Boga y Patí. En el caso del Surubí, del orden del 60 por ciento son triacilgliceroles y el resto fosfolípidos. El contenido de colesterol de la carne de los pescados de agua dulce analizados no pasa de 4,7 mug por gramo de músculo para el Patí y es menor para los otros ejemplares estudiados. Los pescados considerados resultan ser una buena fuente de ácidos grasos polinosaturados tanto n-6 como n-3 para la dieta de la población mediterránea del país. (AU)

Effect of dietary eicosapentaenoic and docosahexaenoic free acids on human plasma phospholipid and triacylglycerol

Durante dos meses se estudió la absorción e incorporación en humanos de los ácidos grasos de la serie n-3, eicosa-5,8,11,14,17-pentenoico y docosa-4,7,10,13,16,19-hexenoico, en fosfolípidos y triacilgliceeroles del plasma. Ambos ácidos n-3 libres se absorbieron regularmente e immediatamente se observó un aumento de dichos ácidos en los contenidos de fosfolípidos y triacilgliceroles del plasma. Al cesar la administración de ácidos grasos n-3, se agotaron rápidamente los depósitos de dichos ácidos

Effect of dietary eicosapentaenoic and docosahexaenoic free acids on human plasma phospholipid and triacylglycerol

Durante dos meses se estudió la absorción e incorporación en humanos de los ácidos grasos de la serie n-3, eicosa-5,8,11,14,17-pentenoico y docosa-4,7,10,13,16,19-hexenoico, en fosfolípidos y triacilgliceeroles del plasma. Ambos ácidos n-3 libres se absorbieron regularmente e immediatamente se observó un aumento de dichos ácidos en los contenidos de fosfolípidos y triacilgliceroles del plasma. Al cesar la administración de ácidos grasos n-3, se agotaron rápidamente los depósitos de dichos ácidos (AU)