title: On the mechanism for PPAR agonists to enhance ABCA1 gene expression.
abstract: Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ogata
authors.forename: Maki
authors.initials: M
authors.lastname: Tsujita
authors.forename: Mohammad Anwar
authors.initials: MA
authors.lastname: Hossain
authors.forename: Nobukatsu
authors.initials: N
authors.lastname: Akita
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Shogo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Genjiro
authors.initials: G
authors.lastname: Kimura
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D045744:Cell Line, Tumor; D011345:Fenofibrate / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011422:Propionates / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C425931:GW 501516; C479889:LY 518674; D047494:PPAR delta; D047495:PPAR gamma; D011422:Propionates; D013844:Thiazoles; D045162:Thiazolidinediones; D014230:Triazoles; D015248:Gemfibrozil; D011345:Fenofibrate; D000077205:Pioglitazone; D001629:Bezafibrate