Targeting mitochondria as central mediators of liver injury in nonalcoholic steatohepatitis: novel treatment implications

• Applicant: Professor Dr. Christian Rust
• Subject Area: Gastroenterology
• Term: from 2012 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 223984975

Nonalcoholic fatty liver disease (NAFLD) is now recognized as one of the most common causes of liver disease in Europe with a prevalence of up to 30%. While the prognosis appears good for pure steatosis, a significant risk of progression towards cirrhosis and, possibly, hepatocellular carcinoma is associated with the presence of inflammation and hepatocellular cell death which are characteristically found in patients with nonalcoholic steatohepatitis (NASH). However, the pathophysiology of NASH is still incompletely understood. Only recently mitochondrial dysfunction has been considered a key player for the development and progression of NASH. Patients with NASH present severe structural mitochondrial alterations, like megamitochondria, impaired hepatic ATP synthesis and increased ROS production. Fatal consequences are a dysregulated liver homeostasis, lipid peroxidation, cytokine release and ultimately cell death, which can occur by apoptosis and regulated necrosis, which has been termed necroptosis. Cell death products are potentially able to activate inflammasomes which might be important for disease progression. Unfortunately, a detailed molecular definition of mitochondrial dysfunction in the pathophysiology of NASH is still lacking. This is of utmost importance, since specific pharmacologic treatments for this disease are still not available.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Hans Zischka