In metabolic syndrome-associated liver diseases, the role of interaction between proteins and lipids and the mechanisms underlying the development of lipid-associated liver diseases, especially of lipid associated hepatocarcinogenesis, are less understood and represent a major focus of our research group.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the main obesity-related cancer in men. Various molecular HCC classifications and signatures of HCC subtypes have been established.

Steatohepatitis, which is a necroinflammatory liver disease, is of high clinical relevance. Depending on the etiology alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) can be morphologically and genetically differentiated. NASH-associated HCC is increasingly found already at pre-cirrhotic stages. ASH and NASH are characterized by disturbed keratin intermediate filament architecture in hepatocytes containing cytoplasmic hepatocytic aggregates, termed Mallory-Denk bodies (MDBs). MDBs are mainly composed of keratin 8, keratin 18, sequestosome 1 (p62), and ubiquitin. Dysbalanced keratins change the lipid profile of hepatocytes and keratin aggregates are critical for MDB formation. Thus, we are interested in the contribution of keratins in steatohepatitis, their impact on hepatocarcinogenesis, and in elucidating the underlying pathways. Preliminary data show that keratins strongly influence hepatic lipid homeostasis.

In the past, the interference with protein translation as molecular target for development of new therapeutics in cancer therapy has played a minor role. We now assume that the old concept of targeting protein synthesis with inhibitors as chemotherapeutics might be of high interest in case of HCC treatment, in particular steatohepatitis-associated HCCs.

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