Hepatic organic anion transporting polypeptide transporter... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Hepatic organic anion transporting polypeptide transporter and thyroid hormone receptor interplay determines cholesterol and glucose homeostasis

Schwabedissen, Henriette E. Meyer zu1; Ware, Joseph A.3,6; Finkelstein, David4; Chaudhry, Amarjit S.5; Mansell, Sara1; Leon-Ponte, Matilde1; Strom, Stephen C.6; Zaher, Hani3; Schwarz, Ute I.1,2; Freeman, David J.2; Schuetz, Erin G.5; Tirona, Rommel G.1,2; Kim, Richard B.1,2

1_Division of Clinical Pharmacology, Department of Medicine, London, ON, Canada_

2_Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada_

3_Pfizer Global Research and Development, Ann Arbor, MI_

4_Information Sciences Department, St. Jude Children's Research Hospital, Memphis, TN_

5_Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN_

6_Department of Pathology, University of Pittsburgh, Pittsburgh, PA_

Wayne State University, Detroit, MI

Genentech, Inc. San Francisco, CA

Institute of Pharmacology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany

Address reprint requests to: Department of Medicine, LHSC-University Hospital, 339 Windermere Road, London, ON, N6A 5A5, Canada. E-mail:[email protected]

Abstract

The role of organic anion transporting polypeptides (OATPs), particularly the members of OATP1B subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B subfamily, we have demonstrated previously that genetic ablation causes reduced hepatic clearance capacity for substrates. In this study, we focused on the physiological function of the hepatic OATP1B transporters. First, we studied the influence of the Oatp1b2 deletion on bile acid (BA) metabolism, showing that lack of the transporter results in a significantly reduced expression of Cyp7a1, the key enzyme of BA synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2 −/− mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2 −/− mice exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK) in knockout mice. We show that this phenotype is due to the loss of liver-specific Oatp1b2-mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR), including Cyp7a1 and Pepck but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers in which OATP1B1 expression was noted to be highly associated with TR target genes, especially for glucose facilitating transporter 2 (GLUT2). Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1. Conclusion: Our findings reveal that OATP1B-mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis. (Hepatology 2011;)