Localization of ammonia-metabolizing enzymes in human liver: Ontogenesis of heterogeneity

Abstract

Immunohistochemical analysis of human liver (8 to 94 years) shows a compartmentation of ammonia-metabolizing enzymes across the acinus. The highest concentration of carbamoylphosphate synthetase (ammonia) is found in the parenchymal cells around the terminal portal venules. Glutamine synthetase is found in a small pericentral compartment two to three cells thick. In contrast to observations in rat liver, in human liver a well-recognizable intermediate zone can be distinguished in which neither enzyme can be detected. This intermediate zone is not yet established at the age of 8 years but can be recognized in livers from 25 years onward. Carbamoylphosphate synthetase can already be detected in the liver of human fetuses at 5 weeks of development. The enzyme distribution reveals a random heterogeneity among the hepatocytes, suggesting that not all hepatocytes start to accumulate carbamoylphosphate synthetase at the same time. From 9 weeks of development onward, the enzyme becomes homogeneously distributed throughout the liver parenchyma until at least 2 days after birth. Glutamine synthetase cannot be detected during this period. In addition, the definitive architecture of the acinus is not yet completed at birth. These results therefore support the idea that in human liver, metabolic zonation with respect to NH3 metabolism exists as it does in rat liver. Furthermore, the data show that this functional compartmentation becomes established concomitant with the development of the acinar architecture.(ABSTRACT TRUNCATED AT 250 WORDS)

Human Umbilical Cord Blood as a Source of Transplantable Hepatic Progenitor Cells

“…GS mRNA, as well as ALB mRNA, was detected in 9 of 10 samples from different donors, CK-18 mRNA was detected in 4 of 10 samples, and AFP mRNA was seen in 2 of 10 samples. GS is known to be expressed in mature hepatocytes [19,20], CK-18 is expressed in the hepatocyte lineage [21,22], and AFP is expressed in hepatic progenitor cells, including oval cells [23,24]. These previous reports support our findings that the cultured cells had the same characteristics as the hepatocyte lineage.…”

Pathologic diagnosis of early hepatocellular carcinoma: A report of the international consensus group for hepatocellular neoplasia

“…50 It is known that glutamine, the end product of GS activity, is the major energy source of tumor cells. 51 Most importantly, GS is a target gene of ␤-catenin so that its overexpression is associated with mutations of ␤-catenin or with activation of this pathway. [52][53][54] Up-regulation of GS messenger RNA, protein, and activity were shown by Christa et al 52 in human HCC, while Osada et al 55 reported the stepwise increase in GS immunoreactivity from precancerous lesions to early HCC to progressed HCC.…”

Pivotal role of glutamine synthetase in ammonia detoxification

“…(42) Accordingly, periportal hepatocytes are well equipped to take up and metabolize glutamine (4,27) because they express the glutamine transporter SLC38A5, (35) glutaminase-2 (EC 3.5.1.2), (43,44) and all enzymes of the urea cycle. (45,46) The trans-membranous Na 1 gradient mediates the uptake of >70% of plasma glutamine and causes it to accumulate intracellularly to 3-5 mmol/ kg. (35,47) A further pH-dependent 4-fold to 5-fold concentrative transport of glutamine occurs across the mitochondrial membrane (47,48) to accommodate the relatively high Michaelis constant of glutaminase-2 in situ (6 mmol/L).…”