Role of NLRP3-inflammasome and ER-stress in NAFLD-Progression.

• Applicant: Professor Dr. Ali Canbay, since 4/2017
• Subject Area: Gastroenterology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255344367

Non alcoholic fatty liver disease (NAFLD) is currently the most prevalent liver disease in Western societies with a prevalence of up to 35%. Non-alcoholic steatohepatitis (NASH), the chronic-progressive manifestation of NAFLD is associated with liver cirrhosis and hepatocellular cancer (HCC). Obesity is associated with a pro-inflammatory state, inducing peripheral lipolysis. Cytokine expression and insulin resistance are widely accepted as underlying mechanisms, promoting hepatic steatosis and inflammation. Though, the underlying mechanisms of progression from simple steatosis to NASH are still not known. The applicant could already show a correlation between hepatic cell death and progression from NAFL to NASH in several studies on cell death markers. Altered cell death was followed by massive liver tissue inflammation which may be due to altered NLRP3 inflammasome activation and ER stress. Preliminary data indicate an increased activation of NLRP3 inflammasome and corresponding target genes in liver tissue of NASH patients compared to patients with NAFL. To elucidate the role of NLRP3 inflammasome and enhanced ER stress in NAFLD progression we will analyze different primary murine and human cells (Kupffer cells and hepatic stellate cells) in vitro, a murine in vivo NASH model as well as liver samples from NAFLD patients. Stool samples will be collected from the in vivo model and patients for analysis of the gut microbiome (richness and composition of bacterial species). The aim is to investigate if NLRP3 inflammasome activation and enhanced ER stress induce inflammation, pro-fibrotic activation as well as different cell death types (apoptosis, pyroptosis, necroptosis) involved in the progression from NAFLD. In addition the effect of an altered microbiome on inflammasome activity and ER stress will be elucidated.

• DFG Programme: Research Grants
• International Connection: USA
• Participating Persons: Professor Dr. Hideo A. Baba; Professor Dr. Jan Buer; Professor Dr. Ariel E. Feldstein
• Ehemaliger Antragsteller: Professor Dr. Guido G.H. Gerken, from 1/2017 until 4/2017