Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse.
Disruption of the murine mdr2 gene leads to the complete absence of biliary phospholipids. We tested the hypothesis that the increase in biliary phospholipid output induced by fibrates is mediated via induction of the hepatic mdr2 gene and its encoded product, the P-glucoprotein canalicular flippase. Increased levels of mdr2 mRNA were observed in the liver of mice treated with different fibrates: ciprofibrate, 660+/-155% (as compared with control group); clofibrate, 611+/-77%; bezafibrate, 410+/-47%; fenofibrate, 310+/-52%; gemfibrozil, 190+/-25% (P <0.05 compared with control group). Induction of expression of the mdr gene family was specific to the mdr2 gene. Two- to three-fold increases in P-glycoprotein immunodetection were evident on the canalicular plasma-membrane domain of clofibrate- and ciprofibrate-treated mice. Biliary phospholipid output increased from 4.2+/-1.2 nmol/min per g of liver in the control group to 8.5+/-0.6, 7.1+/-2.9 and 5.8+/-2.5 in ciprofibrate-, clofibrate- and bezafibrate-treated mice respectively (P <0.05 compared with control group). Moreover, a significant correlation between biliary phospholipid output and the relative levels of mdr2 mRNA was found (r=0.86; P <0.05). In treated animals, bile flow as well as cholesterol and bile acid outputs remained unchanged. Our findings constitute the first evidence that pharmacological modulation of biliary lipid secretion mediated by fibrates can be related to the overexpression of a specific liver gene product, the mdr2 P-glycoprotein, and are consistent with the hypothesis that the mdr2 P-glycoprotein isoform plays a crucial role in the secretion of biliary phospholipid.
Chianale
J
J
Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago.
Vollrath
V
V
Wielandt
A M
AM
Amigo
L
L
Rigotti
A
A
Nervi
F
F
Gonzalez
S
S
Andrade
L
L
Pizarro
M
M
Accatino
L
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D001629:Bezafibrate / Q000494:pharmacology; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001648:Bile Canaliculi / Q000187:drug effects / Q000502:physiology*; D002994:Clofibrate / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D017931:DNA Primers; D018432:Drug Resistance, Multiple / Q000235:genetics*; D011345:Fenofibrate / Q000494:pharmacology; D058607:Fibric Acids; D015248:Gemfibrozil / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D005810:Multigene Family; D010743:Phospholipids / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012337:RNA, Ribosomal, 18S / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D058607:Fibric Acids; D000960:Hypolipidemic Agents; D010743:Phospholipids; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; D002995:Clofibric Acid; C019304:ciprofibrate; D002994:Clofibrate; D015248:Gemfibrozil; D011345:Fenofibrate; D001629:Bezafibrate