title: Cholesterol reduction and atherosclerosis inhibition by bezafibrate in low-density lipoprotein receptor knockout mice.
abstract: Fibrates, peroxisome proliferator-activated receptor a agonists, are widely used as lipid-lowering agents with anti-atherogenic activity. However, conflicting results have been reported with regard to their pharmacological effects on plasma lipoprotein profiles as well as on atherosclerosis in animal models. Furthermore, the anti-atherogenic effects of bezafibrate, one of the most commonly used fibrates, in animal models have not been reported. In the present study, we investigated the effects of bezafibrate on lipoprotein profiles as well as on atherosclerosis in low-density lipoprotein receptor knockout (LDLR-/-) mice fed an atherogenic diet for 8 weeks. Bezafibrate decreased plasma levels of both cholesterol and triglycerides (TG), while increasing plasma levels of high-density lipoprotein-cholesterol (HDL-C). Since hepatic TG production was significantly reduced in the bezafibrate-treated mice lacking LDLR, the plasma lipid-lowering effects of bezafibrate might be primarily mediated by the suppression of hepatic production of apolipoprotein-B-containing lipoproteins. In parallel with the reduced ratio of non-HDL-C to HDL-C, bezafibrate suppressed fatty streak lesions in the aortic sinus by 51%. To determine whether or not bezafibrate directly alters the expression of genes relevant to atherosclerosis, we measured mRNA expression levels of three genes in the aorta by real-time PCR: ATP-binding cassette transporter A1, lipoprotein lipase, and monocyte chemoattractant protein-1. The results showed that there were no differences in the expression of these genes between mice treated with bezafibrate and those not. In conclusion, bezafibrate inhibits atherosclerosis in LDLR-/- mice primarily by decreasing the ratio of non-HDL-C to HDL-C.
authors: Division of Endocrinology and Metabolism, Jichi Medical University School of Medicine, Shimotsuke, Japan.
authors: Toshihiro
authors: T
authors: Inaba
authors: Hiroaki
authors: H
authors: Yagyu
authors: Naoki
authors: N
authors: Itabashi
authors: Fumiko
authors: F
authors: Tazoe
authors: Nobuya
authors: N
authors: Fujita
authors: Shu-ichi
authors: S
authors: Nagashima
authors: Koji
authors: K
authors: Okada
authors: Mitsuyo
authors: M
authors: Okazaki
authors: Yusuke
authors: Y
authors: Furukawa
authors: Shun
authors: S
authors: Ishibashi
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001629:Bezafibrate / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D004195:Disease Models, Animal; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D008055:Lipids; D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides; D008071:Lipoprotein Lipase; D001629:Bezafibrate