Fibrates: What Have We Learned in the Past 40 Years?

James M. Backes, Pharm.D.; Cheryl A. Gibson, Ph.D.; Janelle F. Ruisinger, Pharm.D.; Patrick M. Moriarty, M.D.

Disclosures

Pharmacotherapy. 2007;27(3):412-424. 

In This Article

Mechanism of Action

The mechanism of action of fibrates is complex, involving numerous steps in the metabolism of lipoproteins. Primarily, these agents affect the peroxisome proliferator-activated receptor (PPAR)-α.[3,4] The PPARs are a group of nuclear receptors responsible for modulating numerous metabolic effects, including glucose homeostasis, lipid metabolism, insulin resistance, and hypertension. The PPAR-α is highly expressed in liver, heart, kidney, and muscle tissue, in which it induces the β-oxidation of fatty acids. Fibrates act as synthetic ligands for PPAR-α, transmitting signals from lipid-soluble factors (e.g., fatty acids) to genes in the cell nucleus. The PPAR-α activation regulates the expression of genes involved in multiple metabolic pathways including lipid metabolism, ultimately reducing plasma triglyceride concentrations and increasing high-density lipoprotein cholesterol (HDL) concen-trations. The pharmacologic activation of PPAR-α inhibits the hepatic synthesis of triglycerides and very low-density lipoprotein cholesterol (VLDL). In addition, fibrates produce a PPAR-α–mediated increased expression of lipoprotein lipase and a decreased expression of apolipo-protein (apo) C-III.[4,5] The major responsibility of lipoprotein lipase is intravascular lipolysis of triglycerides from chylomicrons and VLDL, whereas apo C-III is an inhibitor of lipoprotein lipase activity. Thus, the actions of fibrates on lipoprotein lipase and apo C-III further contribute to a reduction in plasma triglyceride concentrations.

The stimulation of PPAR-α also positively influences HDL.[3,4] The two major apolipo-proteins for HDL are apo A-I and apo A-II. Fibrate therapy has demonstrated an increase in the transcription of apo A-I and apo A-II, resulting in a rise in HDL concentrations. The HDL concentrations are also increased by fibrates secondary to the reduction in plasma triglyceride concentrations from the increased activity of lipoprotein lipase.[5] Fibrates also appear to stimulate reverse cholesterol transport by modulating macrophage cholesterol efflux, cholesterol transport, and bile acid synthesis, ultimately enhancing HDL concentrations.[4]

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