Nuclear ErbB2 Expression of Hepatocytes in Alcoholic Steatohepatitis as Response to Cellular Stress Events

Background:

ErbB2 is a prominent member of the epidermal growth factor receptor superfamily, a group of transmembrane receptors that mainly attract attention as oncogenic drivers and therapeutic targets in cancer. Besides transmembrane signaling, ErbB2 may also translocate into the nucleus and mediate distinct nuclear signaling effects, including DNA repair and cell cycle arrest.

Methods:

The immunohistochemical pattern of ErbB2 staining was analyzed in 334 liver biopsy samples from patients with hepatic dysfunction.

Results:

We found a cytoplasmic and nuclear ErbB2 expression in hepatocytes from different disease conditions, with the strongest expression being detected in alcoholic steatohepatitis. These ErbB2 overexpressing hepatocytes revealed peculiar metabolic and hormonal changes: enhanced lipid turnover (increase of fatty acid synthase and acyl-CoA-dehydrogenase), downregulation of estrogen receptor, cell cycle alterations (increase of p21 and heat shock protein 27), and an increase of phospho-Stat3, a downstream effector of nuclear ErbB2 signaling. Notably, ballooned hepatocytes, often interpreted as degenerative cells, exhibited a particularly strong ErbB2 expression and appeared to be highly metabolically active as described above. Of note, an increased ErbB2 expression as well as metabolic alterations and signs of cell cycle deregulation similar to that described in human steatohepatitis specimens were detected when HepG2 cells were subjected to 48-hour ethanol treatment.

Discussion:

These novel observations on hepatocellular ErbB2 expression with evidence of nuclear receptor signaling and metabolic alterations imply a so far unknown mechanism in hepatocytes upon cellular stress events, particularly ethanol exposure. This molecular reprogramming might improve cellular survival, have a significant effect on disease course with therapeutic implications and play a role in progression to hepatocellular carcinoma and thus opens a wide field of future research on the role of hepatocellular ErbB2 expression.

Corresponding author: Döring, Paula

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