Effects of fibrate drugs on expression of ABCA1 and HDL biogenesis in hepatocytes.
Fibric acid-shaped drugs raise high-density lipoprotein (HDL) cholesterol by upregulating the HDL-related genes through activating peroxisome proliferater activated receptor (PPAR)-alpha. We investigated the effects of fibrates to induce expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) and increase HDL biogenesis in hepatocytes. Fenofibrate, bezafibrate, gemfibrozil, and LY518674 were tested for HepG2 cells and primary-cultured mouse hepatocytes. All the compounds examined increased ABCA1 expression and HDL biogenesis dependent on PPARalpha in association with the liver X receptor alpha upregulation. While fenofibrate and LY518674 showed exclusive dependency on PPARalpha for these activities, bezafibrate and gemfibrozil exhibited dependency on PPARbeta/delta and PPARgamma as well. On the other hand, cholesterol-enrichment of HDL may involve PPARgamma for fenofibrate and bezafibrate, and PPARbeta/delta for the fibrates examined except for bezafibrate. We concluded that fibrates enhance expression of ABCA1 in hepatocytes to contribute to increase of the HDL biogenesis in a PPAR-dependent manner, whether exclusively or nonexclusively on PPARalpha.
Hossain
Mohammad Anwar
MA
Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Tsujita
Maki
M
Gonzalez
Frank J
FJ
Yokoyama
Shinji
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology; D015248:Gemfibrozil / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000096:biosynthesis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000960:Hypolipidemic Agents; C479889:LY 518674; D008075:Lipoproteins, HDL; D047492:Peroxisome Proliferator-Activated Receptors; D011422:Propionates; D014230:Triazoles; D015248:Gemfibrozil; D011345:Fenofibrate; D001629:Bezafibrate