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6th Global Summit on Toxicology and Applied Pharmacology

Houston, USA

Bangyan Stiles

Bangyan Stiles

University of Southern California, USA

Title: Regulation of liver drug transporter MRP2 by LKB and PTEN

Biography

Biography: Bangyan Stiles

Abstract

Liver kinase B 1 (LKB1 or STK11) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) are two tumor suppressors that both regulate the mTOR signaling pathway. Deletion studies show that loss of either Stk11 or Pten leads to liver injury. In this study, we investigated the molecular mechanisms underlying such toxicity. We show here that the hepatocyte transporter for bilirubin, multidrug resistant protein (MRP2) is significantly affected by LKB1 loss, correlating with the increases in plasma bilirubin levels. Both the levels and localization of MRP2 are altered by LKB1 loss. MRP2 levels are significantly reduced as a result of LKB1 loss in the liver of Stk11 (LKO) or Stk11/Pten (LPKO) double deleted mice vs. the controls. MRP2 is a multi-drug resistant transporter localized to the canalicular membrane of hepatocytes in the control. MRP2 functions to transport various molecules across the apical membrane including bilirubin. In the LKO and LPKO livers, the canalicular localization of MRP2 is lost and became diffusely localized to both nucleus and the cytoplasm. This observed regulation of MRP2 by LKB1 likely contributed to the lack of cellular polarity and the early lethality phenotype associated with LKO mice.