Atorvastatin and fenofibrate have comparable effects on VLDL-apolipoprotein C-III kinetics in men with the metabolic syndrome.
ABSTRACT The metabolic syndrome (MetS) is characterized by insulin resistance and dyslipidemia that may accelerate atherosclerosis. Disturbed apolipoprotein (apo) C-III metabolism may account for dyslipidemia in these subjects. Atorvastatin and fenofibrate decrease plasma apoC-III, but the underlying mechanisms are not fully understood.
The effects of atorvastatin (40 mg/d) and fenofibrate (200 mg/d) on the kinetics of very-low density lipoprotein (VLDL)-apoC-III were investigated in a crossover trial of 11 MetS men. VLDL-apoC-III kinetics were studied, after intravenous d(3)-leucine administration using gas chromatography-mass spectrometry and compartmental modeling. Compared with placebo, both atorvastatin and fenofibrate significantly decreased (P<0.001) plasma concentrations of triglyceride, apoB, apoB-48, and total apoC-III. Atorvastatin, not fenofibrate, significantly decreased plasma apoA-V concentrations (P<0.05). Both agents significantly increased the fractional catabolic rate (+32% and +30%, respectively) and reduced the production rate of VLDL-apoC-III (-20% and -24%, respectively), accounting for a significant reduction in VLDL-apoC-III concentrations (-41% and -39%, respectively). Total plasma apoC-III production rates were not significantly altered by the 2 agents. Neither treatment altered insulin resistance and body weight.
Both atorvastatin and fenofibrate have dual regulatory effects on VLDL-apoC-III kinetics in MetS; reduced production and increased fractional catabolism of VLDL-apoC-III may explain the triglyceride-lowering effect of these agents.
Article: Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.[show abstract] [hide abstract]
ABSTRACT: Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARalpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARalpha activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARalpha in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.Journal of Clinical Investigation 07/2001; 107(11):1423-32. · 15.39 Impact Factor
Article: Influence of atorvastatin on apolipoprotein E and AI kinetics in patients with type 2 diabetes.[show abstract] [hide abstract]
ABSTRACT: Atorvastatin reduces both plasma cholesterol and triglyceride concentrations in patients with type 2 diabetes, but mechanisms underlying triglyceride decrease and the effect of atorvastatin on high density lipoprotein (HDL) still remain unclear. Apolipoprotein (apo) E plays a crucial role in modulating production and clearance of triglyceride-rich very low density lipoprotein (VLDL). The main effect of apoAI is to modulate HDL metabolism. The aim of this work was to study the influence of atorvastatin on apoAI and apoE kinetics and to determine whether its hypocholesterolemic and hypotriglyceridemic effects could be related to changes in this apolipoprotein metabolism. Plasma VLDL-apoE, HDL-apoE, and HDL-apoAI were studied in seven patients with diabetes with mixed hyperlipidemia using a stable isotope labeling technique ([(2)H3]leucine-primed constant infusion) and monocompartmental model before and after 2 months of treatment with 40 mg/day of atorvastatin. Plasma apoE concentration was significantly reduced (44.1 +/- 19.1 versus 32 +/- 11.6 mg/l, p < 0.05) after treatment. This decrease was associated with a diminution of HDL-apoE concentration (17.46 +/- 6.71 versus 13.37 +/- 6.05 mg/l, p < 0.05) and production rate (0.202 +/- 0.085 versus 0.119 +/- 0.047 mg/kg/day, p < 0.05), whereas an increase in VLDL-apoE concentration (6.44 +/- 2.16 before versus 9.23 +/- 4.02 mg/l after, p < 0.05) and production rate (0.827 +/- 0.367 versus 1.524 +/- 0.664 mg/kg/day, p < 0.05) was observed. No significant difference was observed after treatment for apoAI parameters. We conclude that atorvastatin treatment promotes different apoE distribution between HDL and VLDL, favoring VLDL apoE content. The increased number of apoE per VLDL particle suggests that atorvastatin could enhance the direct catabolism of triglyceride-rich VLDL through apoE receptor pathways.Journal of Pharmacology and Experimental Therapeutics 11/2005; 315(1):363-9. · 3.83 Impact Factor
Article: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis.[show abstract] [hide abstract]
ABSTRACT: Low-density lipoprotein (LDL) is the most abundant and the most atherogenic class of cholesterol-carrying lipoproteins in human plasma. The level of plasma LDL is regulated by the LDL receptor, a cell surface glycoprotein that removes LDL from plasma by receptor-mediated endocytosis. Defects in the gene encoding the LDL receptor, which occur in patients with familial hypercholesterolemia, elevate the plasma LDL level and produce premature coronary atherosclerosis. The physiologically important LDL receptors are located primarily in the liver, where their number is regulated by the cholesterol content of the hepatocyte. When the cholesterol content of hepatocytes is raised by ingestion of diets high in saturated fat and cholesterol, LDL receptors fall and plasma LDL levels rise. Conversely, maneuvers that lower the cholesterol content of hepatocytes, such as ingestion of drugs that inhibit cholesterol synthesis (mevinolin or compactin) or prevent the reutilization of bile acids (cholestyramine or colestipol), stimulate LDL receptor production and lower plasma LDL levels. The normal process of receptor regulation can therefore be exploited in powerful and novel ways so as to reverse hypercholesterolemia and prevent atherosclerosis.Circulation 10/1987; 76(3):504-7. · 14.74 Impact Factor