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Paradoxical severe decrease in serum HDL-cholesterol after treatment with a fibrate.

A O Olukoga
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BezafibrateCholesterol, HDLHumansHypolipidemic AgentsNephritis, InterstitialCommentLetter

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A O Olukoga. 2002. Paradoxical severe decrease in serum HDL-cholesterol after treatment with a fibrate.. https://doi.org/10.1136/jcp.55.9.718-a

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PubMed2003

Correction of fatty acid oxidation in carnitine palmitoyl transferase 2-deficient cultured skin fibroblasts by bezafibrate.

Carnitine palmitoyltransferase 2 (CPTII) deficiency is among the most common inborn errors of mitochondrial fatty acid beta-oxidation (FAO). Clinical phenotype varies in relation to the metabolic block, as assessed by studies of FAO in patient fibroblasts. Thus, fibroblasts from patients with mild manifestations have appreciable residual CPTII enzyme activity, in contrast to those from severely affected patients. In the present study, we hypothesized that the hypolipidemic drug bezafibrate, acting as an activator of the peroxisome proliferator-activated receptor alpha might stimulate FAO in CPTII-deficient cells. Data obtained show that bezafibrate treatment of mild-type CPTII-deficient cells resulted in a time- and dose- dependent increase in CPTII mRNA (from +47% to +66%) and residual enzyme activity (from +54% to 135%), and led to normalization of 3H-palmitate and 3H-myristate cellular oxidation rates. Bezafibrate did not correct FAO in fibroblasts from patients with severe phenotype. This study establishes for the first time that peroxisome proliferator-activated receptor activators, acting via stimulation of gene expression, can stimulate CPTII residual activity to a level sufficient to allow normal FAO flux in deficient human fibroblasts, and suggests that this approach should be tested in other inborn errors of mitochondrial beta-oxidation.

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PubMed2003

Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells.

The effects of a variety of fibrates on the cell viability were examined in human embryonal rhabdomyosarcoma cells (HRMSC). Five fibrates, including fenofibrate, clofibrate, gemfibrozil, bezafibrate and ciprofibrate, all concentration-dependently reduced the cell viability determined by the mitochondrial enzyme activity. The cell injury occurred time-dependently and was marked at 24-48 h. The toxic action of fibrates was specific to HRMSC, since bezafibrate did not induce any marked changes in the viability of human microvascular endothelial cells or arterial smooth muscle cells. Synergistic cell injury was observed after a combined treatment with bezafibrate and simvastatin, although simvastatin alone reduced the cell viability. The cell injury was characterized by a typical nuclear damage, as evidenced by Hoechst 33342 staining and deoxynucleotidyl transferase dUTP nick-end label-positive staining. Similar cell-specific injury was induced by 8(S)-hydroxyeicosatetraenoic acid, a potent peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. Consistent with these data, a marked expression for PPARalpha mRNA was observed in HRMSC but not in the endothelial or smooth muscle cells. Therefore, it is suggested that fibrates cause a cell-specific injury in HRMSC via activation of PPARalpha. Moreover, our present cell injury model using HRMSC may be useful for elucidating the mechanisms of clinical rhabdomyolysis induced by lipid-lowering agents.

Bezafibrate↗
PubMed2003

Inhibition of TNF-alpha-induced RANTES expression in human hepatocyte-derived cells by fibrates, the hypolipidemic drugs.

Increased concentrations and activity of plasma cytokines produced by monocytes, macrophages, and hepatocytes in patients with alcoholic liver diseases, correlate with the clinical course of liver diseases and are of prognostic value. Especially, high levels of circulating tumor necrosis factor (TNF)-alpha have been found to correlate with increased mortality in alcoholic hepatitis. Moreover, hepatic RANTES was increased in patients with alcoholic hepatitis. Thus, TNF-alpha-induced RANTES expression may have a critical role in cell-mediated liver injury associated with alcoholic hepatitis. Fibrates are widely used in the treatment of hyperlipidemia and lower triglyceride levels in patients with hyperlipidemia. Recently, several groups reported that bezafibrate, one of fibrates, is effective in primary biliary cirrhosis treatment. Additionally, it is reported that bezafibrate is effective in the treatment not only of primary biliary cirrhosis but also of chronic hepatitis C and tamoxifen-induced non-alcoholic steatohepatitis. We, here, presented that bezafibrate and fenofibrate repressed TNF-alpha-induced protein production and mRNA expression of RANTES in human hepatocyte-derived cells. Luciferase assay showed that bezafibrate and fenofibrate inhibited RANTES gene expression in response to TNF-alpha. Moreover, bezafibrate repressed TNF-alpha-induced DNA-binding activity of NF-kappaB. Thus, fibrates reduced TNF-alpha-induced NF-kappaB activation and RANTES expression, possibly suggesting that fibrates might be inhibitory agents of migration of inflammatory cells by RANTES to the liver in patients with alcoholic liver diseases. In line of these results, it might be possible that fibrates are therapeutic agents in alcoholic liver diseases.

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