Institute for Pathology, Cologne University Hospital and
CECAD Research Center, University of Cologne, 
Cologne, Germany
Website Kondylis group

Program

"Autophagy-dependent regulation of hepatocyte survival and liver disease progression"

Hepatocellular injury plays a central role in the development of chronic liver disease (CLD), including alcoholic and metabolic dysfunction-associated steatohepatitis (ASH and MASH) and viral hepatitis, thereby predisposing to cirrhosis and hepatocarcinogenesis. Our group is interested in understanding the mechanisms that regulate hepatocyte death and survival.

Autophagy is an intracellular catabolic process that maintains cellular homeostasis and acts as a prosurvival mechanism under both normal and stress conditions. Impaired autophagy has been linked to CLD pathogenesis in mouse models and in humans with ASH and MASH. To investigate this further, we use a mouse model of liver parenchymal cell-specific autophagy impairment (ATG16L1 LPC-KO), which exhibits typical features of liver disease, including spontaneous liver injury, hepatomegaly, hepatitis, fibrosis and liver cancer development. Similar to the presence of Mallory-Denk bodies observed in CLD patients, hepatocytes in ATG16L1 LPC-KO mice display accumulation of cytoplasmic aggregates containing the autophagy receptor Sequestosome-1/p62. Through genetic studies, we found that the aberrant accumulation of p62 under conditions of hepatic autophagy impairment partly mediates liver injury and hepatocarcinogenesis via overactivation of Nrf2 signalling. In search for additional pathways involved in hepatocellular injury, we have recently focused on the role of Type I interferon signalling. Our results indicate that Ifnar1 engagement in LPCs significantly contributes to liver damage, with IFN production being induced via a Mavs-dependent, but Sting-independent pathway. Interestingly, the absence of Zbp1, an IFN-inducible protein that regulates apoptosis and necroptosis, did not provide any protection against liver injury. The potential stimuli that could induce IFN-mediated cell death are currently being investigated in our mice and during liver disease stage transition in patients with MASLD/MASH, while our aim is to eventually establish an autophagy-dependent signature in the plasma samples.

Host: Ulrike RESCH

Contact for questions: Helmut KUBISTA