Arne Dikkers1, Jan Freark de Boer1, Albert K Groen2, Uwe J F Tietge3. 1. Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: u_tietge@yahoo.com.
Abstract
BACKGROUND AND AIMS: Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT. METHODS: Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic Abcg5/g8 overexpression in wild-types. RESULTS: In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p < 0.001), while mass FSE and RCT were unchanged. Hepatic reinstitution of Abcg8 increased biliary cholesterol secretion 5-fold (p < 0.001) without changing FSE or overall RCT. Overexpression of both ABCG5/G8 elevated biliary cholesterol secretion 5-fold and doubled FSE (p < 0.001) without affecting overall RCT. CONCLUSIONS: ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic Abcg5/g8 expression for enhancing RCT are not likely to be successful.
BACKGROUND AND AIMS: Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT. METHODS: Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic Abcg5/g8 overexpression in wild-types. RESULTS: In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p < 0.001), while mass FSE and RCT were unchanged. Hepatic reinstitution of Abcg8 increased biliary cholesterol secretion 5-fold (p < 0.001) without changing FSE or overall RCT. Overexpression of both ABCG5/G8 elevated biliary cholesterol secretion 5-fold and doubled FSE (p < 0.001) without affecting overall RCT. CONCLUSIONS:ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic Abcg5/g8 expression for enhancing RCT are not likely to be successful.
Authors: Annabelle Rodriguez; Bernardo L Trigatti; Chieko Mineo; Darcy Knaack; John T Wilkins; Daisy Sahoo; Bela F Asztalos; Samia Mora; Marina Cuchel; Henry J Pownall; Corina Rosales; Pascal Bernatchez; Amanda Ribeiro Martins da Silva; Godfrey S Getz; Jacob L Barber; Gregory C Shearer; Angela M Zivkovic; Uwe J F Tietge; Frank M Sacks; Margery A Connelly; Michael N Oda; W Sean Davidson; Mary G Sorci-Thomas; Tomas Vaisar; Giacomo Ruotolo; Kasey C Vickers; Catherine Martel Journal: Arterioscler Thromb Vasc Biol Date: 2019-10-10 Impact factor: 8.311
Authors: Reinout L P Roscam Abbing; Davor Slijepcevic; Joanne M Donkers; Rick Havinga; Suzanne Duijst; Coen C Paulusma; Johan Kuiper; Folkert Kuipers; Albert K Groen; Ronald P J Oude Elferink; Stan F J van de Graaf Journal: Hepatology Date: 2019-08-13 Impact factor: 17.425