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

非酒精性脂肪性肝病（NAFLD）是全世界最常见的慢性肝病，在发达国家的患病率估计为25%。肝脏作为中枢代谢器官，是全身性代谢性炎性疾病的触发点和靶结构。在代谢综合征（MS）中，肝脏、肠道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。在多发性硬化症与NAFLD慢性炎症的相互作用中，多效Th2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的发生。另一方面，IL-13的减少伴随着对其他器官系统的多重副作用，这可能间接促进NASH的发生。我们已经证明，在敲除小鼠中关闭IL-13信号可以改善胆汁淤滞和肝纤维化，并恢复肠道完整性和菌群。这导致了一种假设，即肝脏特异性抑制IL-13信号通路是必要的，以便通过这种细胞因子抑制NASH和NASH纤维化的发生或进展。本应用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可能的肝保护作用的病理生理和分子原因，我们将通过组织特异性方法在小鼠NASH模型（西方饮食）中研究IL-13的体内应用或IL-13失活。通过C57BL/6J遗传背景的Lrat-Cre （HSC）、Vil-Cre（肠细胞）和IL- 13r α1扭曲小鼠系，通过Cre-lox系统实现IL-13受体Rα1细胞特异性遗传失活。细胞培养（原代肝细胞和细胞系）的机制分析应阐明IL-13信号调节对HSC转分化、肝细胞代谢和上皮屏障功能的影响。此外，将研究基于细胞和器官特异性调节IL-13信号的联合治疗方案的有效性。反过来说，对NASH患者的人类样本的进一步发现，例如通过肝脏物质的免疫组织学分析，有待证实。从长远来看，在肠细胞和肝星状细胞（HSC）中同时抑制IL-13信号的系统性诱导IL-13可能是一种优化的靶向联合治疗NAFLD的方法。

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.