Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids
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 iPLA2...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
06 September 2017
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| In: |
Biochimica et biophysica acta
Year: 2017, Volume: 1862, Issue: 12, Pages: 1520-1533 |
| ISSN: | 1878-2434 |
| DOI: | 10.1016/j.bbalip.2017.09.001 |
| Online Access: | Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S1388198117301865 Verlag, Volltext: http://dx.doi.org/10.1016/j.bbalip.2017.09.001 
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| Author Notes: | Li Jiao, Hongying Gan-Schreier, Xingya Zhu, Wang Wei, Sabine Tuma-Kellner, Gerhard Liebisch, Wolfgang Stremmel, Walee Chamulitrat |
| Summary: | 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. |
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| Item Description: | Available online 06 September 2017 Gesehen am 28.08.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1878-2434 |
| DOI: | 10.1016/j.bbalip.2017.09.001 |