Peroxisome proliferation fibrates

Fibrates work by reducing apolipoproteins B, C-III (an inhibitor of LPL), and E, and increasing apolipoproteins A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-a), a nuclear receptor involved in cellular function. The changes in these apolipoproteins result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL. 

Peroxisome proliferator-activated receptors (PPARs) PPREs Regulate multiple aspects of lipid metabolism Activated by fibrates and thiazolidinediones Zinc finger... 

Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-a, which modulates the expression of several proteins. LPL, lipoprotein lipase VLDL, very-low-density lipoproteins. 

Various chemicals, such as the fibrate (e.g., clofibrate, bezafibrate, and ciprofibrate) and other lipid-lowering drugs (e.g., Wy-14643) and phthalate plasticizers (e.g., diethylhexyl phthalate), bind to and activate PPARa and are also hepa to carcinogenic in rodents. However, different compounds bind with different affinities, from strong (e.g., Wy-14643) to weak (e.g., phthalates). Thus, it is believed that peroxisomal proliferators act via the receptor (PPARa) to cause some of the effects seen. 

Fibrates (such as clofibrate) are hypolipidemic drugs. They cause a number of biological and biochemical effects, including enzyme induction, peroxisomal proliferation, liver hypertrophy and hyperplasia, and liver cancer. The mechanism is believed to be mediated through the PPARa receptor. Animals lacking this receptor do not show these effects. 

The exact mechanism of these drugs is unclear, but they probably work by binding to a specific nuclear receptor known as the peroxisome proliferator activated receptor.52,141 This receptor, found primarily in the liver and adipose tissues, affects the transcription of genes that affect lipid metabolism.89 Fibrates activate this receptor, thereby mediating several changes at the nuclear level that ultimately cause a decrease in triglycerides and other beneficial changes in plasma lipid metabolism.30,52 In a manner similar to the statins, fibrates may also exert anti-inflammatory, antioxidant, and other beneficial effects in addition to their positive effects on plasma lipids.42,49... 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

Issemann I, Prince RA, Tugwood JD, et al. 1993. The peroxisome proliferator-activated receptor retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol 1137-47. 

Fibrates activate peroxisome proliferator-activated receptors, which are intracellular receptors that cause the transcription of a number of genes on the DNA that facilitate lipid metabolism. They are well absorbed from the gastrointestinal tract (with the exception of medium-acting fenofibrate), display a high degree of binding to albumin, are metabolized by CYP3A4 and are primarily excreted via kidneys there is thus some increase in half-life in patients with severe renal impairment. 

Fig. 1. Chemical structures of different fibrate drugs known to be peroxisomal proliferators (PP) and of neuroactive drugs. Note that WY-14,643 is a fibrate drug and a potent PP but is not used clinically.

Fibrates are classified as peroxisomal proliferators (PPs), as these drugs increase the number and size of cellular peroxisomes not only in the liver but also in many other tissues of susceptible species17,21. Peroxisomes are single membrane bound organelles... 

Staels, B., Schoonjans, K., Fruchart, J. C., and Auwerx, J. (1997). The effects of fibrates and thiazoli-dinediones on plasma triglyceride metabolism are mediated by distinct peroxisome proliferator activated receptors (PPARs). Biochimie 79, 95-99. 

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