The PPARα Agonists Fenofibrate and CP-778875 Cause Increased β-Oxidation, Leading to Oxidative Injury in Skeletal and Cardiac Muscle in the Rat

Abstract

Weak peroxisome proliferator-activated receptor (PPAR) a agonists (fibrates) are used to treat dyslipidemia. This study compared the effects of the potent and selective PPARa agonist CP-778875 on peroxisomal b-oxidation and cardiac and/or skeletal muscle injury with those of the weak PPARa agonist fenofibrate. We hypothesized that these muscle effects are mediated through the PPARa receptor, leading to increased b-oxidation and consequent oxidative stress. CP-778875 (5 or 500 mg/kg) and fenofibrate (600 or 2,000!1,200 mg/kg, dose lowered because of intolerance) were administered to rats for six weeks. Standard end points, serum troponin I, heart and skeletal muscle b-oxidation of palmitoyl-CoA, and acyl co-oxidase (AOX) mRNA were assessed. Both compounds dose-dependently increased the incidence and/or severity of cardiomyocyte degeneration and necrosis, heart weight, troponin I, and skeletal muscle degeneration. Mean heart b-oxidation (3.4-to 5.1-fold control) and AOX mRNA (2.4-to 3.2-fold control) were increased with CP-778875 500 mg/kg and both doses of fenofibrate. b-Oxidation of skeletal muscle was not affected by either compound; however, a significant increase in AOX mRNA (1.6-to 2.1-fold control) was observed with CP-778875 500 mg/kg and both doses of fenofibrate. Taken together, these findings were consistent with PPARa agonism and support the link between increased cardiac and skeletal muscle b-oxidation and resultant muscle injury in the rat.

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

“…However, it remains unclear, at least in cardiovascular tissues, whether this increased lipid oxidation would subsequently lead to oxidative stress due to the augmented respiration. There is evidence that activation of PPARα in the heart either by transgenic overexpression or PPARα selective ligand treatment causes increased fatty acid oxidation [48,49] . Activation of PPARα may be associated with the repression of estrogen related receptors (ERRs).…”

Anti-Hyperlipidemic Effects and Potential Mechanisms of Action of the Caffeoylquinic Acid-Rich Pandanus tectorius Fruit Extract in Hamsters Fed a High Fat-Diet

“…Activation of PPARα by ligands upregulates the expression of genes involved in fatty acid transport and oxidation, such as acyl-CoA oxidase (ACO) [11], [12], carnitine palmitoyl transferase 1 (CPT1) [13], [14], [15], fatty acid transport protein (FATP) [16], [17], hormone-sensitive lipase (HSL) [18], [19], and lipoprotein lipase (LPL) [20], [21]. By altering transcription of these genes, activated PPARα leads to increased breakdown of triglycerides and fatty acids, increased cellular fatty acid uptake, and reduced triglyceride and fatty acid synthesis.…”

Supplementation with the Extract of Schisandrae Fructus Pulp, Seed, or Their Combination Influences the Metabolism of Lipids and Glucose in Mice Fed with Normal and Hypercholesterolemic Diet

“…Although much effort has been put to develop drugs used for the prevention and treatment of HLD-related diseases, effective drugs for treating HLD, especially NAFLD, are yet to be discovered. In addition, synthetic lipid-lowering drugs have many potential adverse/side effects, such as muscle tenderness [10, 11], renal failure [12], and others, including headache, bowel upset, nausea, sleep disturbances, and hepatomegaly [13, 14]. In recent years, people prefer to use natural remedy such as dietary supplement/functional food for the prevention and treatment of NAFLD and/or lipid disorders [15, 16].…”