title: Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in mice: a novel peroxisome proliferator-activated receptor alpha-independent mechanism.
abstract: The triglyceride-lowering effect of bezafibrate in humans has been attributed to peroxisome proliferator-activated receptor (PPAR) alpha activation based on results from rodent studies. However, the bezafibrate dosages used in conventional rodent experiments are typically higher than those in clinical use (> or =50 versus < or =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 PPARalpha 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 PPARalpha-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 beta-oxidation via PPARalpha 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 PPARalpha 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.
authors.affiliation: Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Takero
authors.initials: T
authors.lastname: Nakajima
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kanbe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hara
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kamijo
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D011897:Random Allocation; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*
chemical_list: D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D001629:Bezafibrate