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LIVER AND BILIARY TRACT

Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes

¹INSERM, U680; ²Université Pierre et Marie Curie, Faculté de Médecine; ³AP-HP, Hôpital Saint-Antoine, Département d'Anesthésie-Réanimation Chirurgicale, Paris, France; ⁴Hôpital Universitaire de Genève, Département d'Anesthésie-Réanimation, Genève, Suisse; ⁵AP-HP, Hôpital Saint-Antoine, Fédération de Biochimie; ⁶AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique; ⁷AP-HP Hôpital Tenon, Service d'Anatomie Pathologique, Paris; ⁸Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, Lyon; ⁹AP-HP, Hôpital Tenon, Service de Biochimie-Hormonologie, Paris, France

Submitted 27 April 2006 ; accepted in final form 13 March 2007

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., HNF4, RXR, 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.

liver ischemia; cholestasis; Na⁺-taurocholate-cotransporting polypeptide; bile salt export pump; multidrug resistance-associated protein 2; cystic fibrosis transmembrane conductance regulator

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