Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids

• Verfasst von: Jiao, Li [VerfasserIn]
• Verfasst von: Gan-Schreier, Hongying [VerfasserIn]
• Verfasst von: Zhu, Xingya [VerfasserIn]
• Verfasst von: Wei, Wang [VerfasserIn]
• Verfasst von: Tuma-Kellner, Sabine [VerfasserIn]
• Verfasst von: Stremmel, Wolfgang [VerfasserIn]
• Verfasst von: Chamulitrat, Walee [VerfasserIn]
• Titel: Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids
• Verf.angabe: Li Jiao, Hongying Gan-Schreier, Xingya Zhu, Wang Wei, Sabine Tuma-Kellner, Gerhard Liebisch, Wolfgang Stremmel, Walee Chamulitrat
• E-Jahr: 2017
• Jahr: 06 September 2017
• Umfang: 14 S.
• Fussnoten: Available online 06 September 2017 ; Gesehen am 28.08.2018
• Titel Quelle: Enthalten in: Biochimica et biophysica acta
• Ort Quelle: Amsterdam [u.a.] : Elsevier, 1947
• Jahr Quelle: 2017
• Band/Heft Quelle: 1862(2017), 12, Seite 1520-1533
• ISSN Quelle: 1878-2434
• DOI: doi:10.1016/j.bbalip.2017.09.001
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Ageing
• Sach-SW: FXR
• Sach-SW: Intestinal homeostasis
• Sach-SW: Lipidomics
• Sach-SW: Pla2G6
• Sach-SW: XBP1
• K10plus-PPN: 1580437559

Abstract

Ageing is a major risk factor for various forms of liver and gastrointestinal (GI) disease and genetic background may contribute to the pathogenesis of these diseases. Group VIA phospholipase A2 or iPLA2β is a homeostatic PLA2 by playing a role in phospholipid metabolism and remodeling. Global iPLA2β−/− mice exhibit aged-dependent phenotypes with body weight loss and abnormalities in the bone and brain. We have previously reported the abnormalities in these mutant mice showing susceptibility for chemical-induced liver injury and colitis. We hypothesize that iPLA2β deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA2β−/− mice at 4 and 20-22months of age were studied. Aged, but not young, iPLA2β−/−mice showed increased hepatic fibrosis and biliary ductular expansion as well as severe intestinal atrophy associated with increased apoptosis, pro-inflammation, disrupted tight junction, and reduced number of mucin-containing globlet cells. This damage was associated with decreased expression of intestinal endoplasmic stress XBP1 and its regulator HNF1α, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXRα and FXR. By LC/MS-MS profiling, iPLA2β deficiency in aged mice caused an increase of intestinal arachidonate-containing phospholipids concomitant with a decrease in ceramides. By the suppression of intestinal FXR/FGF-15 signaling, hepatic bile-acid synthesis gene expression was increased leading to an elevation of secondary and hydrophobic bile acids in liver, bile, and intestine. In conclusions, ageing sensitized by iPLA2β deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut-to-liver manner.