Modulation of Metabolic Zonation of Glutamine Synthetase and Cytochrome P-4502E1 in Hepatic Fibrosis of Aged Cadavers

Abstract

AIMS: Expression of glutamine synthetase (GS) and cytochrome P-4502E1 (CYP2E1) are notable physiological processes characterizing hepatic metabolic zonation. It is unknown whether liver fibrogenesis modulates GS zonation. CYP2E1 is upregulated in liver fibrogenesis. The present study evaluated metabolic zonation of GS and CYP2E1 in progressive stages of liver fibrosis and whether their expressions were correlated.

Methods: 32 cadaveric livers (mean age, 84.8 ± 1.9) with minimal fibrosis, septal fibrosis, bridging fibrosis, incomplete cirrhosis and cirrhosis were studied. Consecutive paraffin sections were immunostained for GS or CYP2E1. GS-positive hepatocytes in perivenous and non-perivenous areas were presented as numbers per central vein and staining scores. Zonal distribution of CYP2E1 was scored.

RESULTS: GS-positive hepatocytes increased as fibrosis progressed cumulating in a significantly higher count at the bridging fibrosis stage. The increase was primarily attributed to a greater perivenous hepatocyte GS expression with minor contribution from non-perivenous cells. There was a significantly higher incidence of GS immunoreactivity in the non-perivenous area at the bridging fibrosis stage. GS expression was variable in incomplete cirrhosis and negligible in cirrhosis. GS-positive cell numbers correlated with their staining scores. CYP2E1 zonation was centrilobular and midlobular and occasionally periportal. CYP2E1 immunoreactivity was diffuse in nodular hepatocytes of cirrhosis. Staining scores of GS and CYP2E1 were not correlated.

CONCLUSIONS: Increased GS metabolic zonation may reflect a regenerative cellular response to liver injury caused by fibrosis and/or aging-related pathologies. While CYP2E1 expression shows little changes in fibrosis progression, it may have a role in effectuating aging-related hepatic pathologies.