Ageing sensitized by iPLA2β 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.


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*


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