Modulation of Membrane Phospholipids by Hepatic Deficiency of iPLA2beta Renders Hepatitis Susceptibility in Non-obese but Protects against Steatosis in Obese Mice

iPLA2beta 肝缺陷对膜磷脂的调节使非肥胖小鼠易患肝炎，但可防止肥胖小鼠发生脂肪变性

• 批准号: 249280891
• 负责人: Dr. Walee Chamulitrat, Ph.D.
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Infektionskrankheiten, Vergiftungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/249280891?language=en
• 关键词: Modulation; Membrane; Phospholipids; Hepatic; Deficiency

Calcium-indepedent phospholipase A2 (PLA2) VIA or iPLA2beta catalyzes the hydrolysis of a phospholipid to lysophospholipid which is thought to play a role in macrophage signalling and PL remodeling of epithelial cells. Our work in the first DFG period has shown that whole-body iPLA2beta deficiency induces hypometabolism in decreasing hepatic lipids, and this in turn elicits protection against obesity and fatty liver. However, in non-obese mice iPLA2beta deficiency represents a 'sensitized' state rendering susceptibility for fulminant hepatitis as well as microbial- and age-dependent development of fibrosis and hepatocellular carcinoma. In this renewal application, we hypothesize that these pathological events may be related to the preferential hydrolysis by iPLA2beta towards aminophospholipids, namely, phosphatidylethanolamine (PE) and phosphatidylserine (PS), since their levels are accumulated in iPLA2beta-deficient livers. By using isolated hepatocytes, we will determine whether this accumulation would lead to an increase in PE and PS externalized to the membrane outer leaflets, thus being prone for oxidation to PE/PS aldehydes. Externalization of PE and PS is an early event in apoptosis, we will determine if iPLA2beta deficiency sensitizes TNF-alpha-induced apoptosis with a mechanism involving PE/PS externalization. Since PE (but not PS) is known as a lipid receptor for the binding of gram-negative bacteria in host cells, we will also determine whether externalized PE binds to Helicobacter Hepaticus, as these bacteria can induce hepatitis and sensitize HCC in susceptible mouse strains. By using hepatocyte-specific iPLA2beta-knockout mice with the deletion of exons 6-8, we will further determine the changes in hepatic PL profiles, PE/PS aldehydes, and externalized PE and PS upon in vivo administration with H. Hepaticus LPS, diethylnitrosamine, and high-fat diet as a model of hepatitis, hepatocellular carcinoma, and obesity, respectively.Our research highlights iPLA2beta as a gene that modulates membrane PL whereby its deficiency increases inflammation susceptibility in non-obese but protects fatty liver in obese mice. The understanding of this contrasting scenario in the modulation of membrane PL may be used as a therapeutic basis for treatment of hepatitis and fatty liver in humans.

钙依赖性磷脂酶A2（PLA 2）VIA或iPLA 2 β催化磷脂水解为溶血磷脂，溶血磷脂被认为在巨噬细胞信号传导和上皮细胞的PL重塑中起作用。我们在第一个DFG阶段的工作表明，全身iPLA 2 β缺乏诱导降低肝脏脂质的代谢减退，这反过来又有助于预防肥胖和脂肪肝。然而，在非肥胖小鼠中，iPLA 2 β缺乏代表了一种“致敏”状态，导致对暴发性肝炎以及纤维化和肝细胞癌的微生物和年龄依赖性发展的易感性。在本更新申请中，我们假设这些病理事件可能与iPLA 2 β对氨基磷脂（即磷脂酰乙醇胺（PE）和磷脂酰丝氨酸（PS））的优先水解有关，因为它们的水平在iPLA 2 β缺乏的肝脏中积累。通过使用分离的肝细胞，我们将确定这种蓄积是否会导致外化至膜外小叶的PE和PS增加，从而易于氧化为PE/PS醛。PE和PS的外化是细胞凋亡的早期事件，我们将确定iPLA 2 β缺乏是否通过涉及PE/PS外化的机制使TNF-α诱导的细胞凋亡敏感。由于PE（而不是PS）被认为是宿主细胞中革兰氏阴性菌结合的脂质受体，我们还将确定外部PE是否与肝螺杆菌结合，因为这些细菌可以诱导肝炎并使易感小鼠品系的HCC敏感。通过使用缺失外显子6-8的肝细胞特异性iPLA 2 β敲除小鼠，我们将进一步确定体内给予H后肝脏PL谱、PE/PS醛以及外化PE和PS的变化。我们的研究强调了iPLA 2 β作为一种调节膜PL的基因，其缺陷增加了非肥胖小鼠的炎症易感性，但保护了肥胖小鼠的脂肪肝。对膜PL调节中的这种对比情况的理解可用作治疗人类肝炎和脂肪肝的治疗基础。