title: Sensitization to autoimmune hepatitis in group VIA calcium-independent phospholipase A2-null mice led to duodenal villous atrophy with apoptosis, goblet cell hyperplasia and leaked bile acids.
abstract: Chronic bowel disease can co-exist with severe autoimmune hepatitis (AIH) in an absence of primary sclerosing cholangitis. Genetic background may contribute to this overlap syndrome. We previously have shown that the deficiency of iPLA2β causes an accumulation of hepatocyte apoptosis, and renders susceptibility for acute liver injury. We here tested whether AIH induction in iPLA2β-null mice could result in intestinal injury, and whether bile acid metabolism was altered. Control wild-type (WT) and female iPLA2β-null (iPLA2β(-/-)) mice were intravenously injected with 10mg/kg concanavalinA (ConA) or saline for 24h. ConA treatment of iPLA2β(-/-) mice caused massive liver injury with increased liver enzymes, fibrosis, and necrosis. While not affecting WT mice, ConA treatment of iPLA2β(-/-) mice caused severe duodenal villous atrophy concomitant with increased apoptosis, cell proliferation, globlet cell hyperplasia, and endotoxin leakage into portal vein indicating a disruption of intestinal barrier. With the greater extent than in WT mice, ConA treatment of iPLA2β(-/-) mice increased jejunal expression of innate response cytokines CD14, TNF-α, IL-6, and SOCS3 as well as chemokines CCL2 and the CCL3 receptor CCR5. iPLA2β deficiency in response to ConA-induced AIH caused a significant decrease in hepatic and biliary bile acids, and this was associated with suppression of hepatic Cyp7A1, Ntcp and ABCB11/Bsep and upregulation of intestinal FXR/FGF15 mRNA expression. The suppression of hepatic Ntcp expression together with the loss of intestinal barrier could account for the observed bile acid leakage into peripheral blood. Thus, enteropathy may result from acute AIH in a susceptible host such as iPLA2β deficiency.
authors.affiliation: Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany; Department of Toxicology, School of Public Health, Jilin University, Changchun, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jiao
authors.affiliation: Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany.
authors.forename: Hongying
authors.initials: H
authors.lastname: Gan-Schreier
authors.affiliation: Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tuma-Kellner
authors.affiliation: Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.affiliation: Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany. Electronic address: Walee.Chamulitrat@med.uni-heidelberg.de.
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001284:Atrophy / Q000209:etiology; D001647:Bile Acids and Salts / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003208:Concanavalin A; D004386:Duodenum / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D020397:Goblet Cells / Q000473:pathology*; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D019693:Hepatitis, Autoimmune / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D006965:Hyperplasia / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability
chemical_list: D001647:Bile Acids and Salts; D003208:Concanavalin A; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse
keywords: Bile acids; Enterohepatic cycle; Enteropathy; Hepatic necrosis; Inflammation; Pla2G6