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

作者：Jiao, Li; Gan-Schreier, Hongying; Zhu, Xingya; Wei, Wang; Tuma-Kellner, Sabine; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Walee^*

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2017, 1862(12): 1520-1533.

DOI：10.1016/j.bbalip.2017.09.001

• P1a2G6
• Ageing
• Intestinal homeostasis
• XBP1
• Lipidomics
• FXR

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.

• 出版日期2017-12
• 单位中国医学科学院北京协和医院; 中国医学科学院医学生物学研究所