Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

Abstract

Hypertriglyceridemia, a key feature of the metabolic syndrome (MetS), is associated with increased risk of cardiovascular disease (CVD) ( 1 ). It is the most consistent lipid disorder in subjects with obesity and type 2 diabetes. Hypertriglyceridemia is primarily related to dysregulated triglyceride-rich lipoprotein (TRL) metabolism, including overproduction of very low-density lipoprotein (VLDL) particles and delayed catabolism of TRL and their remnants ( 2 ). These abnormalities are a collective consequence of insulin resistance and increased lipid substrate availability in the liver, as well as depressed activities of lipoprotein lipase (LPL) and hepatic receptors ( 3 ).Apolipoprotein (apo)E is a 34.2 kDa glycoprotein synthesized by the liver and, to a lesser extent, by peripheral tissues ( 4 ). Clinical studies show that plasma apoE concentration explains 20-40% of the variation in plasma trig lyceride concentrations. A key role of apoE is to act as a high-affi nity ligand for members of the low-density lipoprotein (LDL) receptor family, including the LDL receptor, LDL receptor-related protein (LRP), the VLDL receptor, GP330/Megalin, and ApoER-2. ApoE is also a ligand for heparin sulfate proteoglycans (HSPG). By binding to these hepatic and extrahepactic receptors, apoE mediates the clearance of TRL and their remnants from the circulation ( 5 ). The role of apoE is not confi ned only to the clearance of lipoprotein particles, however. ApoE inhibits LPL-mediated lipolysis of lipoproteins by displacing LPL cofactor apoC-II ( 6, 7 ). ApoE has also been shown to stimulate hepatic secretion VLDL particles; apoEdefi cient mice showed a 50% reduction in VLDL secretion ( 8 ), and hepatic expression of human apoE2, apoE3, and apoE4 stimulated VLDL production in vivo ( 9-12 ). Therefore, apoE is an important determinant of in vivo TRL Abstract We examined the effects of fenofi brate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofi brate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations ( P < 0.05). Fenofi brate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo ( P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR ( P < 0.05). Fenofi brate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofi brate was 22% less than that with atorvastatin ( P < 0.01). With fenofi brate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofi brate decreased VLDL-apoE ...

Absolute Quantification of Apolipoproteins Following Treatment with Omega-3 Carboxylic Acids and Fenofibrate Using a High Precision Stable Isotope-labeled Recombinant Protein Fragments Based SRM Assay

“…In various clinical intervention studies, fenofibrate treatment has shown a consistent increase in apoAII, whereas the effect on apoAI is less consistent (30–36, 59). In this study, fenofibrate treatment increased apoAII significantly, whereas no significant effect on apoAI was observed.…”

“…Prescription grade formulations of omega-3 fatty acids given in doses of 2–4 g usually decrease serum triglycerides (TG) about 30% (24), whereas 160 or 200 mg fenofibrate decrease serum TG about 30–50%. Many studies have investigated the effects of omega-3 fatty acids and fenofibrate on circulating levels of apolipoproteins (25–43). Although apoAI, apoAII and apoB have been extensively studied, the effects of omega-3 fatty acids or fenofibrate on total circulating levels of apoCIV, apoJ (clusterin), apoAIV, apoL1, apoD or apoF have not been investigated in clinical studies to the best of our knowledge.…”

S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease

“…Very-low-density lipoproteins (VLDL) transport triglycerides (TG) from liver to peripheral tissues providing an energy source. Plasma levels of VLDL are defined by the rate of clearance from plasma and the rate of hepatic secretion, so an imbalance between these two processes will lead to dyslipidemia, highly associated with increased risk of cardiovascular disease [1, 2], which is one of the extrahepatic complications of nonalcoholic fatty-liver disease (NAFLD) [3]. Individuals with NAFLD exhibit disrupted VLDL metabolism [4, 5].…”

Interaction Between VLDL and Phosphatidylcholine Liposomes Generates New γ‐LpE‐like Particles

“…It was also demonstrated that lipid-lowering therapy with atorvastatin and fenofibrate leads to reduction of apoE concentration in VLDL [43, 44]. Similarly, the interaction between liposomes and VLDL caused a decrease in the apoE concentration in VLDL (Fig.…”