Understanding of mechanism underlying intracellular sorting of hepatocanalicular transporters

2012 Fiscal Year Final Research Report

• Project/Area Number: 23790175
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: HAYASHI Hisamitsu 東京大学, 大学院・薬学系研究科, 助教 (10451858)
• Project Period (FY): 2011 – 2012
• Keywords: トランスポーター / 肝内胆汁うっ滞 / 細胞内ソーティング / 胆汁酸 / フェニルブ チレート / コレステロール

Research Abstract

Bile salt export pump (BSEP) localizes on canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. BSEP dysfunction attributed to its internalization from hepatocanalicular membrane and subsequent degradation causes intrahepatic cholestasis. At present, no medical therapy for this disease state has been established, because the regulatory mechanism of cell surface expression of BSEP remains to be elucidated. In this study, we explored it focusing on posttranslational machinery and demonstrated that ubiquitination, a posttranslational modification, of BSEP plays a role in its internalization via clathrin-mediated endocytosis involving the AP2 adaptor complex,an adaptor protein required for cargo selection in clathrin-mediated endocytosis.

Research Products

• [Journal Article] E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: structural development study and separation from farnesoid X receptor-agonistic activity. (2012)
  • Author(s): Misawa T, Hayashi H, Makishima M, Sugiyama Y, Hashimoto Y.
  • Journal Title: Bioorg Med Chem Lett. Volume: 22(12) Pages: 3962-6
• [Journal Article] Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2. (2012)
  • Author(s): Misawa T, Hayashi H, Sugiyama Y, Hashimoto Y.
  • Journal Title: Bioorg Med Chem. Volume: 20(9) Pages: 2940-9
• [Journal Article] AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function. (2012)
  • Author(s): Hayashi H, Inamura K, Aida K, Naoi S, Horikawa R, Nagasaka H, Takatani T, Fukushima T, Hattori A, Yabuki T, Horii I, Sugiyama Y.
  • Journal Title: Hepatology. Volume: 55(6) Pages: 1889-900
• [Journal Article] 4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration. (2012)
  • Author(s): Hayashi H, Mizuno T, Horikawa R, Nagasaka H, Yabuki T, Takikawa H, Sugiyama Y.
  • Journal Title: J Hepatol. Volume: 56(5) Pages: 1136-44
• [Journal Article] Ubiquitination is associated with lysosomal degradation of cell surface-resident ABCA1 through the ESCRT pathway. (2011)
  • Author(s): Mizuno T, Hayashi H, Naoi S, Sugiyama Y
  • Journal Title: Hepatology. Volume: 54(2) Pages: 631-43
• [Journal Article] Sugiyama Y.Calpain-mediated cleavage negatively regulates the expression level of ABCG1. (2011)
  • Author(s): Hori N, Hayashi H
  • Journal Title: Atherosclerosis. Volume: 215(2) Pages: 383-91