A nuclear receptor-mediated choleretic action of fibrates is associated with enhanced canalicular membrane fluidity and transporter activity mediating bile acid-independent bile secretion.
Fibrates are commonly used lipid-lowering agents that act via PPARalpha, a member of the nuclear hormone receptor superfamily. The mechanism(s) of fibrate-induced changes in the hepatic canalicular membrane and bile lipids are still unknown. Therefore, the aim of this study was to investigate the influence of fibrates on hepatic lipid metabolism and to assess the hepatocellular cytoprotective effect on hepatocyte canalicular membrane. Male ICR mice were fed standard chow with or without bezafibrate (100 mg/kg) for 6 days. The expression of canalicular membrane transporters (Mdr2 and Mrp2) was evaluated by RT-PCR and Western blotting. Canalicular membrane fluidity was also investigated. Canalicular membrane fluidity was markedly increased by fibrates. The expression of mdr 2 and mrp2 mRNA and protein showed a significant increase in fibrate-treated mice. These results suggested that fibrates improve liver function by enhancing bile secretion. The mechanism of the choleretic action of fibrate therapy might involve the enhancement of bile acid-independent bile secretion, since increased expression of Mdr2 and Mrp2 was found in fibrate-treated animals. These changes were very likely mediated by PPARalpha, and the increase of canalicular membrane fluidity may have been partly associated with enhancement of this transporter activity.
Nishioka
Tomoji
T
Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Hyogo
Hideyuki
H
Numata
Yoshihiro
Y
Yamaguchi
Atsushi
A
Kobuke
Toshiya
T
Komichi
Daisuke
D
Nonaka
Michihiro
M
Inoue
Motoki
M
Nabeshima
Yoshitaka
Y
Ogi
Mami
M
Iwamoto
Keiko
K
Ishitobi
Tomokazu
T
Ajima
Takeyoshi
T
Chayama
Kazuaki
K
Tazuma
Susumu
S
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D001629:Bezafibrate; D000960:Hypolipidemic Agents; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4