ReviewThe effect of PPAR-α agonism on apolipoprotein metabolism in humans
Introduction
Cardiovascular disease is the leading cause of death in the world today. The World Health Organization projects that the number of deaths from cardiovascular disease will increase as the incidence of obesity and associated diseases, especially diabetes and metabolic syndrome, continues to rise [1]. Diet and lifestyle changes are recommend as the initial treatment for hypertriglyceridemia and atherogenic dyslipidemia (elevated triglyceride, LDL, and reduced HDL) that are associated with obesity, metabolic syndrome and diabetes. However, in many instances these are ineffective requiring many patients to use lipid altering drugs to improve their plasma lipid levels [2]. Fibric acid derivatives (fibrates) are frequently selected as pharmacologic treatments for atherogenic dyslipidemia and hypertriglyceridemia due to their effects on reducing plasma triglyceride levels and increasing HDL levels.
Fibrates activate the nuclear receptor peroxisome proliferator activated receptor-α (PPAR-α). Activation of PPAR-α leads to changes in transcription of a large number of genes that regulate lipoprotein metabolism including LPL, APOC3, PCSK9, ANGPTL3, APOA1, APOA 2 and APOA5 [3], [4], [5], [6]. Changes in transcription of LPL, APOC3 and APOA5 are thought to lead to enhanced lipolysis of VLDL triglycerides resulting in reduced plasma triglyceride levels while changes in APOA1 and APOA2 transcription are thought to lead to enhanced apoA-I and apoA-II production resulting in increased HDL cholesterol (C) levels. Indeed, a mean increase in HDL-C of up to 23% has been reported with the use of fibrates [3]. Fibrates can effectively reduce triglyceride levels in patients with atherogenic dyslipidemia, dysbetalipoproteinemia (Fredrickson type III) and high to very high triglyceride levels (<400 mg/dL, Fredrickson types I, IV, and V) [7]. Fibrates also influence LDL-C levels and generally reduce LDL-C in patients with plasma triglyceride levels <400 mg/dL. LDL-C levels generally increase with fibrate treatment in those with plasma triglyceride levels of >400 mg/dL [8].
Recently the results of two studies in which patients were treated with novel potent PPAR-α agonists, LY518674 or CP-778,875, were reported [9], [10]. As with fibrates, each of these selective PPAR-α agonists was effective in reducing plasma triglyceride levels. It was also found that these drugs reduced LDL cholesterol levels in patients with triglyceride levels <400 mg/dL but increased LDL in patients with plasma triglyceride levels >400 mg/dL. At lower doses, these drugs raised HDL-C levels to a degree that was similar to fenofibrate. Paradoxically, at higher doses the effect of these drugs on HDL-C levels was more modest or there was no change. The reason that the lower doses had a greater effect on increasing HDL-C levels is not immediately apparent.
A total of fifteen studies have been conducted to assess changes in lipoprotein metabolism in response to treatment with fibrates ([11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]; Table 1). The results often appear conflicting due to the small number of subjects in each study and differences in study design. However, as noted previously [8], [27], patterns emerge when the studies are examined as a group and the patients are categorized according to lipid phenotype. This manuscript reviews data from studies that have measured changes in apolipoprotein kinetics using radioactive and stable isotope tracers in response to treatment with fibrates and also includes data from a recent study that examined the effects of specific PPAR-α agonist on lipoprotein metabolism [28]. This review may prove to be useful in determining the expected response of patients to fibrate treatment and in guiding the development of the next generation of fibrates.
Section snippets
Triglyceride-rich lipoproteins: chylomicron apoB-48 and VLDL apoB-100
Fibrates reduce plasma triglyceride levels by enhancing triglyceride clearance from plasma [8], [27]. This is thought to be a result of their effects of promoting transcription of lipoprotein lipase and repressing transcription of apoC-III, an inhibitor of lipoprotein lipase [3]. Effects on apoA-V and Angptl4, both of which influence lipoprotein lipase activity, may also be contributory [5], [6]. Enhanced VLDL triglyceride lipolysis would be expected to lead to increased clearance of VLDL
Apolipoprotein A-I
Apart from effects on apoB metabolism, fibrates also influence increase HDL metabolism leading to an increase in HDL-C levels in the majority of studies that were of relatively short (<26 weeks) duration. Results from the FIELD Study indicate that the HDL response to fibrate treatment in type 2 diabetic subjects is maximal within 16 weeks of treatment but slowly falls back toward baseline levels over an average of 5 years treatment [38]. The increase in HDL is thought to be due, in part, to
Summary
The well-established triglyceride-lowering effect of fibrates results from enhanced lipolysis of triglyceride-rich VLDL leading to increased catabolism of VLDL apoB-100. There is also evidence that fibrates reduce the VLDL apoB-100 production rate in patients with elevated plasma triglyceride levels. Thus, fibrates lower plasma triglyceride levels primarily by enhancing VLDL catabolism and, to a lesser extent in some patients, by also reducing VLDL production.
While the effects of fibrates on
Conflict of interest statement
Dr. Rader has been a consultant to and/or has received research funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, and Novartis. Dr. Millar has received partial salary support and/or research funding from Abbott Laboratories and Merck.
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