Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids / Li Jiao, Hongying Gan-Schreier, Xingya Zhu, Wang Wei, Sabine Tuma-Kellner, Gerhard Liebisch, Wolfgang Stremmel, Walee Chamulitrat

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..

Medienart:

E-Artikel

Erscheinungsjahr:

06 September 2017

2017

Erschienen:

06 September 2017

Enthalten in:

Zur Gesamtaufnahme - volume:1862

Enthalten in:

Biochimica et biophysica acta - 1862(2017), 12, Seite 1520-1533

Sprache:

Englisch

Beteiligte Personen:

Jiao, Li [VerfasserIn]
Gan-Schreier, Hongying, 1967- [VerfasserIn]
Zhu, Xingya, 1990- [VerfasserIn]
Wei, Wang, 1985- [VerfasserIn]
Tuma-Kellner, Sabine [VerfasserIn]
Stremmel, Wolfgang, 1952- [VerfasserIn]
Chamulitrat, Walee, 1959- [VerfasserIn]

Links:

Volltext
Volltext

Themen:

Ageing
FXR
Intestinal homeostasis
Lipidomics
Pla2G6
XBP1

Anmerkungen:

Available online 06 September 2017

Gesehen am 28.08.2018

Umfang:

14

doi:

10.1016/j.bbalip.2017.09.001

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

1580437559