Glutamine Synthetase and Cytochrome P‐4502E1 Characterize Metabolic Zonation in Human Liver: Immunohistochemical Study

Abstract

Hepatic metabolic zonation endows metabolic homeostasis and proper functioning of the liver under various physiological conditions. The zonation reflects the heterogeneity of gene expression and functions of hepatocytes along the centro‐portal axis of the liver lobule. The Wnt/ß‐catenin signaling pathway is the master regulator of hepatic zonation. The pathway maintains the metabolic zonation of glutamine synthetase (GS) and cytochrome P‐4502E1 (2E1) —among others—in the centrilobular parenchyma. GS detoxifies ammonia entering the liver as well as serves as an immunohistological marker of perivenous hepatocytes that make up the first three cell layers around the central vein. 2E1 mediates metabolism of xenobiotics and has a broader centrilobular expression than that of GS. While the zonation of GS and 2E1 has been documented in animal models, the phenomenon remains to be evaluated in human liver. This study assessed expression of GS and 2E1 in human cadaveric livers by immunohistochemistry. Ten livers of cadavers (mean age, 79.9 years) with minimal fibrotic changes were studied. Consecutive paraffin liver sections were stained with a polyclonal GS antibody or 2E1 antibody using an immunoperoxidase method. The central vein was defined as a hepatic vein located at the center of the classic liver lobule and showed a cross‐sectional diameter not exceeding 150 μm. In each liver, five to six veins were examined for the distribution of GS+ hepatocytes in the centrilobular area. In most cases, GS+ hepatocytes were arranged in a band of 1 to 3 cells wide in the perivenous area around the central veins (perivenous cells). In some instances, GS staining was observed in hepatocytes beyond the perivenous area (recorded as non‐perivenous cells). Midlobular and periportal hepatocytes lacked GS staining. Expressed as per central vein, counts of perivenous GS+ cells were 14.9 ± 2.2 and non‐perivenous cells were 5.6 ± 1.8. The mean 2E1 zonal score was 1.35 ± 0.35. Total GS+ cell numbers (perivenous plus non‐perivenous) were found to correlate with 2E1 zonal scores (P > 0.05, N = 10).ConclusionsExpression of GS and 2E1 characterizes the metabolic zonation in the liver of aged cadavers, in accordance with the findings of animal studies. The correlation of GS with 2E1 expression suggests a link between the hepatic zonation of GS and 2E1, which is consistent with the notion that the zonation is mediated by the Wnt/ß‐catenin signaling pathway.