Control of metabolically induced steatohepatitis (NASH) via modulation of the IL-13 signaling pathway in liver, intestinal, and adipose tissue

通过调节肝脏、肠道和脂肪组织中的 IL-13 信号通路来控制代谢性脂肪性肝炎 (NASH)

• 批准号: 499353576
• 负责人: Professorin Dr. Elke Roeb
• 金额: --
• 依托单位: Arbeitsgruppe Gastroenterologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/499353576?language=en
• 关键词: Control; metabolically; induced; steatohepatitis; NASH

Non-alcoholic fatty liver disease, NAFLD, is the most common chronic liver disease worldwide, with an estimated prevalence of 25% in developed countries. As the central metabolic organ, the liver is trigger and target structure of systemic metabolic-inflammatory diseases. In metabolic syndrome (MS), metabolic-inflammatory interactions between the liver, intestine and adipose tissue lead to the progression of hepatic steatosis to steatohepatitis (NASH) and subsequent NASH fibrosis. Within the interplay between MS and chronic inflammation in NAFLD, the pleiotropic Th2 cytokine IL-13 plays a decisive role in linking metabolic and inflammatory processes. Clinical studies and animal experiments show that a global perturbation of the IL-13 system might delay NASH. On the other hand IL-13 reduction is accompanied by multiple side effects on other organ systems, which then indirectly might promote NASH. We have shown that switching off the IL-13 signaling in knockout mice improves cholestasis and liver fibrosis and restores intestinal integrity and flora. This leads to the hypothesis that liver-specific inhibition of the IL-13 signaling pathway is necessary in order to inhibit the development or progression of NASH and NASH fibrosis via this cytokine. The aim of this application is a systematic comparison of the effects of specific IL-13 receptor mutations in liver and intestinal cells on the development of NAFLD. To clarify the pathophysiological and molecular causes of a putative hepatoprotective effect of IL-13, an IL-13 application or an IL-13 inactivation in vivo by tissue-specific approaches in a murine NASH model (Western diet) will be investigated. The cell-type-specific genetic deactivation of the IL 13 receptor Rα1 via the Cre-lox system will be achieved by crossing Lrat-Cre (HSC), Vil-Cre (enterocytes) and IL-13Rα1-twisted mouse lines on the genetic background C57BL/6J. Mechanistic analyzes in cell culture (primary liver cells and cell lines) should clarify the effects of a modulation of IL-13 signaling on transdifferentiation of HSC, hepatocyte metabolism and epithelial barrier function. In addition, the effectiveness of combined therapy options based on cell and organ-specific modulations of IL-13 signaling will be investigated. Translationally, further findings on human samples from NASH patients, e.g. by immunohistological analyzes of liver material, are to be proven. The systemic induction of IL-13 with simultaneous inhibition of IL-13 signaling in enterocytes and hepatic stellate cells (HSC) could represent an optimized and targeted combination therapy for NAFLD in the long term.

非酒精性脂肪性肝病（NAFLD）是全球最常见的慢性肝病，在发达国家估计患病率为25%。肝脏作为中枢代谢器官，是全身性代谢-炎症性疾病的触发和靶向结构。在代谢综合征（MS）中，肝脏、肠和脂肪组织之间的代谢-炎症相互作用导致肝脂肪变性进展为脂肪性肝炎（NASH）和随后的NASH纤维化。在MS和NAFLD慢性炎症之间的相互作用中，多效性Th 2细胞因子IL-13在连接代谢和炎症过程中起决定性作用。临床研究和动物实验表明，IL-13系统的整体扰动可能会延迟NASH。另一方面，IL-13减少伴随着对其他器官系统的多种副作用，这可能间接促进NASH。我们已经证明，在基因敲除小鼠中关闭IL-13信号传导可以改善胆汁淤积和肝纤维化，恢复肠道完整性和植物群。这导致了这样的假设，即为了通过该细胞因子抑制NASH和NASH纤维化的发展或进展，IL-13信号传导途径的肝脏特异性抑制是必要的。本申请的目的是系统比较肝脏和肠细胞中特异性IL-13受体突变对NAFLD发展的影响。为了阐明IL-13的推定肝保护作用的病理生理学和分子原因，将研究在鼠NASH模型（西方饮食）中通过组织特异性方法的IL-13应用或体内IL-13失活。通过在遗传背景C57 BL/6 J上杂交Lrat-Cre（HSC）、Vil-Cre（肠上皮细胞）和IL-13 R α1-扭曲小鼠系，将实现通过Cre-lox系统的IL-13受体Rα1的细胞类型特异性遗传失活。细胞培养（原代肝细胞和细胞系）中的机制分析应阐明IL-13信号转导对HSC转分化、肝细胞代谢和上皮屏障功能的调节作用。此外，将研究基于IL-13信号传导的细胞和器官特异性调节的联合治疗方案的有效性。在翻译方面，来自NASH患者的人类样品的进一步发现，例如通过肝脏材料的免疫组织学分析，有待证实。在肠上皮细胞和肝星状细胞（HSC）中全身诱导IL-13并同时抑制IL-13信号传导可能代表了长期NAFLD的优化和靶向联合治疗。