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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...

Abstract-Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the apolipoprotein E-deficient (apoEϪ/Ϫ) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. A Medline search reveals over 645 articles dedicated to studies using this reliable and convenient "super" animal model since its inception (Piedrahita JA et al, Proc Natl Acad Sci U S A 1992;89:4471-4475; Plump AS et al, Cell 1992;71:343-353) with a more or less steady increase from year to year. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding. The apoE-deficient (apoEϪ/Ϫ) mouse was created practically simultaneously in two separate laboratories, through gene inactivation by targeting. On a chow diet, the mice demonstrated a total cholesterol level Ͼ500 mg/dL, mostly in the VLDL and chylomicron remnant fractions. A Western diet quadrupled these fractions. 4,5 The apoEϪ/Ϫ mice available today through The Jackson Laboratories are descendants of the original apoEϪ/Ϫ mouse created by the Maeda group (t002052 B6.129P2-Apoetm1Unc). Plaque Pathology in the ApoE؊/؊ MouseFatty streaks were first observed in the proximal aorta of a chow-fed, 3-month-old mouse. 4 On this diet, as early as 10 weeks of age, foam cell lesions were observed by light microscopy. Intermediate lesions containing foam cells and smooth muscle cells were seen at 15 weeks, and fibrous plaques appeared at 20 weeks of age. A Western diet accelerated the process. Histological and morphometric analyses of plaque progression revealed an increase in complexity as well as in lesion size with age ( Figure 1). 6 Although molecular studies of vascular remodeling in these mice had not yet begun, fragmentation of the elastic lamina was well documented, as were calcification and wall thinning in most mice aged at least 32 weeks.Once the presence of plaques resembling human lesions was confirmed, there ensued explosive use of the model in the study of factors affecting plaque size and composition. Two quantitation methods are used extensively to measure plaques. The first measures plaque cross sectional area in slices taken at the level of the aortic sinus, 1 and is useful for mild or early stage disease. The second (increasingly popular) "en face" method involves pinning out the aorta and quantifying lesion area as a percentage of total surface area. 5,7 This method requires older mice, as it appears to be generally agreed on that plaques first appear proximally and only later appear distally. 6,8 Because there is no map of lesion appear-

Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) offer important benefits for the large population of individuals at high risk for coronary heart disease. This population encompasses a sizable portion of individuals who are also at high risk for drug-drug interactions due to their need for multiple medications. In general, statins are associated with a very small risk for myopathy (which may progress to fatal or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is known to increase this risk in specific high-risk groups. The incidence of myopathy associated with statin therapy is dose related and is increased when statins are used in combination with agents that share common metabolic pathways. Of particular concern is the potential for interactions with other lipid-lowering agents such as fibrates and niacin (nicotinic acid), which may be used in patients with mixed lipidemia, and with immunosuppressive agents, such as cyclosporine, which are commonly used in patients after transplantation. Clinicians should be alert to the potential for drug-drug interactions to minimize the risk of myopathy during long-term statin therapy in patients at high risk for coronary heart disease.

Familial hypercholesterolemia (FH) has a frequency of 0.2% in most populations of the world. In selected populations such as the Afrikaners in South Africa, the Christian Lebanese, and the French Canadians, the disease is more frequent due to the founder effect. Previous studies demonstrated that a single mutation at the LDL receptor locus, the so-called French Canadian deletion, makes up 60% of the mutant genes responsible for FH in the French Canadian population. In this study, efforts were directed to determine if there were other common LDL receptor mutations in this population. Three missense mutations were identified and each mutation was reproduced and expressed in vitro. Two of the three mutations result in the production of an LDL receptor protein that is not processed to its mature form at a normal rate. Molecular assays were developed to detect the mutations directly, and the LDL receptor genes of 130 French Canadian FH heterozygotes were screened for the presence of the three missense mutations as well as two deletions. LDL receptor mutations were detected in 76% of individuals and 14% had one of the three missense mutations. (J. Clin. Invest. 1990Invest. . 85:1014Invest. -1023.) familial hypercholesterolemia-LDL receptors hypercholesterolemia