title: Fasting reduces liver fibrosis in a mouse model for chronic cholangiopathies.
abstract: Chronic cholangiopathies often lead to fibrosis, as a result of a perpetuated wound healing response, characterized by increased inflammation and excessive deposition of proteins of the extracellular matrix. Our previous studies have shown that food deprivation suppresses the immune response, which led us to postulate its beneficial effects on pathology in liver fibrosis driven by portal inflammation. We investigated the consequences of fasting on liver fibrosis in Abcb4(-/-) mice that spontaneously develop it due to a lack of phospholipids in bile. The effect of up to 48h of food deprivation was studied by gene expression profiling, (immuno)histochemistry, and biochemical assessments of biliary output, and hepatic and plasma lipid composition. In contrast to increased biliary output in the wild type counterparts, bile composition in Abcb4(-/-) mice remained unchanged with fasting and did not influence the attenuation of fibrosis. Markers of inflammation, however, dramatically decreased in livers of Abcb4(-/-) mice already after 12h of fasting. Reduced presence of activated hepatic stellate cells and actively increased tissue remodeling further propelled a decrease in parenchymal fibrosis in fasting. This study is the first to show that food deprivation positively influences liver pathology in a fibrotic mouse model for chronic cholangiopathies, opening a door for new strategies to improve liver regeneration in chronic disease.
authors.affiliation: University of Amsterdam, Amsterdam, The Netherlands. asokolovic@gmail.com
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Sokolović
authors.forename: Cindy P A A
authors.initials: CP
authors.lastname: van Roomen
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.forename: Johan K
authors.initials: JK
authors.lastname: Hiralall
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.forename: Jan
authors.initials: J
authors.lastname: Aten
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolović
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D015153:Blotting, Western; D002908:Chronic Disease; D004195:Disease Models, Animal; D005215:Fasting; D005705:Gallbladder Diseases / Q000150:complications*; D008055:Lipids / Q000097:blood; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D008055:Lipids
keywords: 36b4; Apaf; BCL2-associated X protein; BCL2-like 1; Bax; Bcl-xl; EGF-like module containing, mucin-like, hormone receptor-like sequence 1; F4/80; Fasting; Gfap; Hprt; Inflammation; Ki67; Liver fibrosis; MFs; Mac1; Matrix remodeling; Mcp1; Mpo; Pcna; Plat; Plau; Tgfβ1; Timp; actin, alpha 2, smooth muscle; antigen identified by monoclonal antibody Ki 67; apoptotic peptidase activating factor 1; chemokine (C-C motif) ligand 2; cyclin-dependent kinase inhibitor 1A; glial fibrillary acidic protein; hypoxanthine guanine phosphoribosyl transferase; integrin alpha M; myeloperoxidase; myofibroblasts; p21; plasminogen activator, tissue; plasminogen activator, urokinase; proliferating cell nuclear antigen; ribosomal protein, large, P0; tissue inhibitor of metalloproteinase; transforming growth factor, beta 1; α-Sma