Ageing sensitized by iPLA 2 β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids

Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Dec;1862(12):1520-1533. doi: 10.1016/j.bbalip.2017.09.001. Epub 2017 Sep 6.

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.

Keywords: Ageing; FXR; Intestinal homeostasis; Lipidomics; Pla2G6; XBP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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