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

• Applicant: Professorin Dr. Elke Roeb
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499353576

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.

• DFG Programme: Research Grants