Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes.
Cholestatic disorders may arise from liver ischemia (e.g., in liver transplantation) through various mechanisms. We have examined the potential of hypoxia to induce changes in the expression of hepatobiliary transporter genes. In a model of arterial liver ischemia subsequent to complete arterial deprivation of the rat liver, the mRNA levels of VEGF, a hypoxia-inducible gene, were increased fivefold after 24 h. The pattern of VEGF-induced expression and ultrastructural changes, including swelling of the endoplasmic reticulum, indicated that hypoxia affected primarily cholangiocytes, but also hepatocytes, predominantly in the periportal area. Serum and bile analyses demonstrated liver dysfunction of cholestatic type with reduced bile acid biliary excretion. Fluorescence-labeled ursodeoxycholic acid used as a tracer displayed no regurgitation, eliminating bile leakage as a significant mechanism of cholestasis in this model. In liver tissue, a marked reduction in the mRNA levels of Na(+)-taurocholate-cotransporting polypeptide (Ntcp), bile salt export protein (Bsep), and multidrug resistance-associated protein 2 (Mrp2) and an increase in those of Cftr were detected before bile duct proliferation occurred. In cultured hepatocytes, a nontoxic hypoxic treatment caused a decrease in the mRNA and protein expression of Ntcp, Bsep, and Mrp2 and in the mRNA levels of nuclear factors involved in the transactivation of these genes, i.e., HNF4alpha, RXRalpha, and FXR. In bile duct preparations, hypoxic treatment elicited an increase in Cftr transcripts, along with a rise in cAMP, a major regulator of Cftr expression and function. In conclusion, hypoxia triggers a downregulation of hepatocellular transporters, which may contribute to cholestasis, whereas Cftr, which drives secretion in cholangiocytes, is upregulated.
Fouassier
Laura
L
INSERM U680, Faculté de Médecine Pierre et Marie Curie, Site Saint-Antoine, 27 rue Chaligny, 75571 Paris Cedex 12, France.
Beaussier
Marc
M
Schiffer
Eduardo
E
Rey
Colette
C
Barbu
Véronique
V
Mergey
Martine
M
Wendum
Dominique
D
Callard
Patrice
P
Scoazec
Jean-Yves
JY
Lasnier
Elisabeth
E
Stieger
Bruno
B
Lienhart
André
A
Housset
Chantal
C
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002779:Cholestasis / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism*; D007511:Ischemia / Q000503:physiopathology; D008099:Liver / Q000098:blood supply; D008297:Male; D027361:Organic Anion Transporters / Q000096:biosynthesis*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000096:biosynthesis*; D014580:Ursodeoxycholic Acid / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D042461:Vascular Endothelial Growth Factor A; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C071908:sodium-bile acid cotransporter; D014580:Ursodeoxycholic Acid