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

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.

• Authors: Li Jiao, Hongying Gan-Schreier, Xingya Zhu, Wang Wei, Sabine Tuma-Kellner, Gerhard Liebisch, Wolfgang Stremmel, Walee Chamulitrat
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1862 Issue 12 Pg. 1520-1533 (Dec 2017) ISSN: 1388-1981 [Print] Netherlands
• PMID: 28888832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Bile Acids and Salts
• Ceramides
• Phospholipids
• Group VI Phospholipases A2
• Pla2g6 protein, mouse

Topics

• Aging (genetics, metabolism, pathology)
• Animals
• Bile Acids and Salts (genetics, metabolism)
• Ceramides (genetics, metabolism)
• Group VI Phospholipases A2 (deficiency)
• Intestinal Diseases (genetics, metabolism, pathology)
• Liver Cirrhosis (genetics, metabolism, pathology)
• Mice
• Mice, Knockout
• Phospholipids (genetics, metabolism)