title: Overexpression of insulin like growth factor binding protein 5 reduces liver fibrosis in chronic cholangiopathy.
abstract: The ATP-binding cassette, sub-family B member 4 knock-out mouse (Abcb4(-/-)) is a relevant model for chronic cholangiopathy in man. Due to the lack of this P-glycoprotein in the canalicular membrane of hepatocytes, the secretion of phospholipids into bile is absent, resulting in increased bile toxicity. Expression of insulin like growth factor binding protein 5 (Igfbp5) increases in time in the livers of these mice. It is unclear whether this induction is a consequence of or plays a role in the progression of liver pathology. The aim of this study was therefore to investigate the effect of IGFBP5 induction on the progression of liver fibrosis caused by chronic cholangiopathy. IGFBP5 and, as a control, green fluorescent protein were overexpressed in the hepatocytes of Abcb4(-/-) mice, using an adeno-associated viral vector (AAV). Progression of liver fibrosis was studied 3, 6, and 12 weeks after vector injection by analyzing serum parameters, collagen deposition, expression of pro-fibrotic genes, inflammation and oxidative stress. A single administration of the AAV vectors provided prolonged expression of IGFBP5 and GFP in the livers of Abcb4(-/-) mice. Compared to GFP control, fractional liver weight, extracellular matrix deposition and amount of activated hepatic stellate cells significantly decreased in IGFBP5 overexpressing mice even 12 weeks after treatment. This effect was not due to a change in bile composition, but driven by reduced inflammation, oxidative stress, and proliferation. Overexpression of IGFBP5 seems to have a protective effect on liver pathology in this model for chronic cholangiopathy.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, The Netherlands. a.sokolovic@amc.uva.nl
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Sokolović
authors.forename: Paula S
authors.initials: PS
authors.lastname: Montenegro-Miranda
authors.forename: Dirk Rudi
authors.initials: DR
authors.lastname: de Waart
authors.forename: Radha M N
authors.initials: RM
authors.lastname: Cappai
authors.forename: Suzanne
authors.initials: S
authors.lastname: Duijst
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolović
authors.forename: Piter J
authors.initials: PJ
authors.lastname: Bosma
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D049109:Cell Proliferation; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D014158:Transcription, Genetic; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003094:Collagen; D049452:Green Fluorescent Proteins; D018975:Insulin-Like Growth Factor Binding Protein 5; D000097202:ATP-Binding Cassette Sub-Family B Member 4