Steatohepatitis is a characteristic type of liver disease which develops in the context of a variety of chronic liver diseases, such as alcoholism (alcoholic steatohepatitis), insulin resistance, obesity and other lipid-associated disorders (non-alcoholic steatohepatitis). Steatohepatitis is becoming a leading health problem affecting approximately 3% of the world population by 2010. However, there is a marked difference in the individual risk to develop steatohepatitis and to progress to cirrhosis (e.g. 20% of heavy drinkers or 50% of obese type II diabetic patients develop steatohepatitis). Several lines of evidence propose the existence of susceptibility and modifier genes that cooperate with lifestyle factors in causing these differences.

Steatohepatitis leads to characteristic morphological alterations in the liver comprising steatosis, ballooning of hepatocytes, occurrence of hepatocytic protein aggregates (Mallory Denk bodies; MDBs), fibrosis and inflammation. Evaluation of these features by liver biopsy is still the gold standard for the diagnosis of steatohepatitis. We identified p62 (sequestosome 1), which is induced under certain stress conditions and specifically binds to misfolded and ubiquitinated keratin, as obligatory component of MDBs. p62 is involved as adapter in signal transduction pathways (e.g. TNFα- and IL-1-signaling leading to NFκB activation), in the sequestration of ubiquitinated proteins and the elimination of protein aggregates by autophagy. This multifunctional role makes p62 a candidate for an essential integrator and regulator of cellular stress responses in protein aggregation diseases.

Curriculum vitae

Publications

Grants