Jiao, Li and Gan-Schreier, Hongying and Zhu, Xingya and Wei, Wang and Tuma-Kellner, Sabine and Liebisch, Gerhard and Stremmel, Wolfgang and Chamulitrat, Walee (2017) Ageing sensitized by iPLA(2)beta deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1862 (12). pp. 1520-1533. ISSN 1388-1981, 0006-3002
Full text not available from this repository. (Request a copy)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 iPLA(2)beta is a homeostatic PLA2 by playing a role in phospholipid metabolism and remodeling. Global iPLA(2)beta(-/-) 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 iPLA(2)beta deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA(2)beta(-/-) mice at 4 and 20-22 months of age were studied. Aged, but not young, iPLA(2)beta(-/-) 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 HNF1 alpha, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXR alpha and FXR. By LC/MS-MS profiling, iPLA(2)beta 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 iPLA(2)beta deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut-to-liver manner.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INDEPENDENT PHOSPHOLIPASE A(2); ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; INFLAMMATORY-BOWEL-DISEASE; NUCLEAR HORMONE-RECEPTORS; FACTOR 1-ALPHA HNF1-ALPHA; OXIDATIVE STRESS; ER STRESS; HEPATIC STEATOSIS; APOPTOTIC CELLS; P1a2G6; Ageing; Intestinal homeostasis; XBP1; Lipidomics; FXR |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:19 |
| Last Modified: | 18 Feb 2019 12:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1808 |
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