Abstract-Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-␣ form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase-mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the ␤-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression. (Circulation. 1998;98:2088-2093.)Key Words: apolipoproteins Ⅲ arteriosclerosis Ⅲ fibrates Ⅲ hypercholesterolemia Ⅲ hyperlipoproteinemia Ⅲ lipids Ⅲ PPAR A vast number of studies confirmed the intimate and causative relationships between dyslipidemias and coronary heart disease. Although hypercholesterolemia is an important underlying cause for coronary heart disease, other dyslipidemias, such as hypoalphalipoproteinemia (low plasma HDL) and hypertriglyceridemia, may be causative in a substantial number of cases. Fibrates are useful for the treatment of hypoalphalipoproteinemia with or without hypertriglyceridemia.1,2 The recommendation for the use of fibrates in certain types of dyslipidemia has gained additional support from a subgroup analysis of the Helsinki Heart Study, 3 which showed that the best preventive efficacy has been achieved in a subset of Ϸ10% of the study population who had a baseline LDL:HDL cholesterol ratio of Ͼ5 and a triglyceride level of 2.3 mmol/L. 4,5 Results from angiographic trials revealed that fibrates retard the progression of coronary atherosclerosis and decrease the number of coronary events. 6,7 Pharmacological Action of FibratesFibrates are generally effective in lowering elevated plasma triglycerides and cholesterol. The magnitude of lipid changes depends, however, on the patient's pretreatment lipoprotein status 8 as well as the relative potency of the fibrate used. 9 The most pronounced effects of fibrates are a decrease in plasma triglyceride-rich lipoproteins (TRLs). Levels of LDL cholesterol (LDL-C) generally decrease in individuals with elevated baseline plasma concentrations, and HDL cholesterol (HDL-C) levels are u...

Comparison of genomic DNA sequences from human and mouse revealed a new apolipoprotein (APO) gene ( APOAV ) located proximal to the well-characterized APOAI/CIII/AIV gene cluster on human 11q23. Mice expressing a human APOAV transgene showed a decrease in plasma triglyceride concentrations to one-third of those in control mice; conversely, knockout mice lacking Apoav had four times as much plasma triglycerides as controls. In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies. These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease.

Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.