Abstract
The triglyceride-lowering effect of bezafibrate in humans has been attributed to peroxisome proliferator-activated receptor (PPAR) α activation based on results from rodent studies. However, the bezafibrate dosages used in conventional rodent experiments are typically higher than those in clinical use (≥50 versus ≤10 mg/kg/day), and thus it remains unclear whether such data can be translated to humans. Furthermore, because bezafibrate is a pan-PPAR activator, the actual contribution of PPARα to its triglyceride-lowering properties remains undetermined. To address these issues, bezafibrate at clinically relevant doses (10 mg/kg/day; low) was administered to wild-type and Ppara-null mice, and its effects were compared with those from conventionally used doses (100 mg/kg/day; high). Pharmacokinetic analyses showed that maximum plasma concentration and area under the concentration-time curve in bezafibrate-treated mice were similar to those in humans at low doses, but not at high doses. Low-dose bezafibrate decreased serum/liver triglycerides in a PPARα-independent manner by attenuation of hepatic lipogenesis and triglyceride secretion. It is noteworthy that instead of PPAR activation, down-regulation of sterol regulatory element-binding protein (SREBP)-1c was observed in mice undergoing low-dose treatment. High-dose bezafibrate decreased serum/liver triglycerides by enhancement of hepatic fatty acid uptake and β-oxidation via PPARα activation, as expected. In conclusion, clinically relevant doses of bezafibrate exert a triglyceride-lowering effect by suppression of the SREBP-1c-regulated pathway in mice and not by PPARα activation. Our results may provide novel information about the pharmacological mechanism of bezafibrate action and new insights into the treatment of disorders involving SREBP-1c.
Footnotes
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This research was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute.
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ABBREVIATIONS: TG, triglyceride; Apo, apolipoprotein; ACC, acetyl-CoA carboxylase; AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration; CPT, carnitine palmitoyl-CoA transferase; FAS, fatty acid synthase; FAT, fatty acid translocase; FATP, fatty acid transport protein; FFA, free fatty acid; FXR, farnesoid X receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPAT, glycerol-3-phosphate acyltransferase; LC/MS/MS, high-performance liquid chromatography/tandem mass spectrometry; LPL, lipoprotein lipase; LXR, liver X receptor; MCAD, medium-chain acyl-CoA dehydrogenase; MTP, microsomal TG transfer protein; PCR, polymerase chain reaction; PDK, pyruvate dehydrogenase kinase; PMP70, 70-kDa peroxisomal membrane protein; PPAR, peroxisome proliferator-activated receptor; SCAP, SREBP cleavage-activating protein; SCD, stearoyl-CoA desaturase; SHP, short heterodimer partner; SREBP, sterol regulatory element-binding protein; Tmax, time to reach Cmax; VLDL, very-low-density lipoprotein.
- Received October 20, 2008.
- Accepted January 5, 2009.
- U.S. Government work not protected by U.S. copyright
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