dinoprost and Hypertriglyceridemia

Although there is evidence that hyperlipidemia and predominance of small dense low density lipoproteins (LDLs) are associated with increased oxidative stress, the oxidation status in patients with hypertriglyceridemia (HTG) has not been studied in detail. Therefore, we studied urinary levels of F(2)-isoprostanes (8-isoprostaglandin F(2alpha) and 2,3-dinor-5,6-dihydro-8-isoprostaglandin F(2alpha)) and susceptibility of very low density lipoproteins (VLDLs) and LDLs to oxidation ex vivo in 18 patients with endogenous HTG and 20 matched control subjects. In addition, the effects of 6 weeks of bezafibrate therapy were assessed in a double-blind, placebo-controlled, crossover trial. Urinary levels of F(2)-isoprostanes were similar in the HTG and normolipidemic group. Bezafibrate caused an increase in 8-isoprostaglandin F(2alpha) (762+/-313 versus 552+/-245 ng/24 h for bezafibrate and placebo therapy, respectively; P=0.03), whereas 2,3-dinor-5, 6-dihydro-8-isoprostaglandin F(2alpha) levels tended to be increased (1714+/-761 versus 1475+/-606 ng/24 h for bezafibrate and placebo therapy, respectively; P=0.11). VLDLs and LDLs were more resistant to copper-induced oxidation in patients with HTG than in control subjects. Bezafibrate reversed the oxidation resistance to the normal range. In conclusion, these results indicate the following: (1) HTG is associated with normal in vivo oxidative stress and enhanced ex vivo resistance of lipoproteins to oxidation. (2) Bezafibrate reduces the resistance of lipoproteins to copper-induced oxidation and enhances oxidative stress in HTG patients.

Topics: Bezafibrate; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Dinoprost; Double-Blind Method; Female; Humans; Hypertriglyceridemia; In Vitro Techniques; Lipid Metabolism; Lipids; Lipoproteins; Lipoproteins, VLDL; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

We examined the associations between intake of different types of dietary fat and plasma levels of oxidative stress and endothelial activation markers in men.. For that purpose, a complete physical and metabolic profile was assessed. Dietary habits of subjects were determined with a 3-d food record. We also measured fasting plasma 8-iso-prostaglandin F2alpha and oxidized low-density lipoprotein concentrations and soluble forms of vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and E-selectin. All these measurements were performed with commercial enzyme-linked immunosorbent assay kits and standards.. We found that a high total dietary fat intake was associated with high plasma sICAM-1 (r = 0.40, P < 0.005), sVCAM-1 (r = 0.31, P < 0.05), and E-selectin (r = 0.28, P < 0.05) levels. We also found that in men matched for plasma triacylglycerol levels, those consuming a diet rich in total fat (>105 g/d, n = 21) were characterized by higher circulating levels of sICAM-1 (P < 0.05) and E-selectin (P < 0.05) compared with triacylglycerol-matched individuals with a low total dietary fat intake (<105 g/d, n = 21). However, no significant difference was noted in plasma oxidized low-density lipoprotein levels between groups. Further, we conducted multivariate analyses and found that saturated fatty acid intake was the only dietary variable after inclusion of other dietary variables that contributed to circulating sICAM-1 (P < 0.05) and sVCAM-1 (P < 0.05).. Our study suggests that high dietary fat consumption is associated with endothelial activation in men and that this detrimental effect is likely attributable to the saturated fatty acid content of the diet.

Topics: Adult; Biomarkers; Diet; Diet Records; Dietary Fats; Dinoprost; E-Selectin; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Humans; Hypertriglyceridemia; Intercellular Adhesion Molecule-1; Lipoproteins, LDL; Male; Multivariate Analysis; Obesity; Oxidative Stress; Vascular Cell Adhesion Molecule-1

Topics: Animals; Aorta; Blood Pressure; Dietary Fats, Unsaturated; Dinoprost; Fish Oils; Hypertriglyceridemia; Male; Muscle Contraction; Norepinephrine; Potassium Chloride; Rats; Rats, Wistar; Vasomotor System