Hepatic clearance of rat liver aspartate aminotransferase isozymes: Evidence for endocytotic uptake via different binding sites on sinusoidal liver cells

Abstract

Rat liver aspartate aminotransferase (AAT) (EC 2.6.1.1) exists in two isozymic forms, cytosolic (c-AAT) and mitochondrial (m-AAT). The previous study (Kamimoto, Y. et al., Hepatology an accompanying paper in this issue) demonstrated that these isozymes were cleared from blood at different half-lives via adsorptive endocytosis by sinusoidal liver cells. To understand the cellular mechanism for the differential uptake of the isozymes, we have further studied in vivo uptake of 125I-labeled AAT isozymes by sinusoidal cells. The results indicated that the uptake of the isozymes occurred via a typical endocytotic pathway: the initial binding, internalization and subsequent degradation in the lysosomes. Quantitation of the isozymes bound to the cell surface prior to internalization either by binding at 4 degrees C or by a combined use of anti-AAT antibody and 125I-protein A at 37 degrees C revealed that the differential plasma clearance of AAT isozymes could be attributable to the isozymic difference in capacity of surface membranes to bind the isozymes. The uptake of 125I-c-AAT was inhibited by unlabeled c-AAT more significantly than by m-AAT, but not by other ligands known to be taken up by sinusoidal cells via receptor-mediated pathways. Similarly, the uptake of 125I-m-AAT was inhibited predominantly by unlabeled m-AAT. Similar ligand specificity was also demonstrated in the binding study at 4 degrees C. The binding of 125I-m-AAT and c-AAT followed saturation kinetics with an apparent Kd of 1.3 X 10(-6) M and 1.7 X 10(-6) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

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Role of AST to platelet ratio index in the detection of liver fibrosis in patients with recurrent hepatitis C after liver transplantation

“…This test includes and combines in a ratio two good indicators of liver fibrosis, AST and platelet count. Progression of liver fibrosis may reduce AST clearance, leading to increased serum levels; 18 in addition, liver disease may be associated with mitochondrial injury, 19 resulting in further AST release from the hepatocytes. The platelet count decreases, in inverse proportion to progressive liver fibrosis, due to worsening of portal hypertension with consequent increased platelet sequestration and destruction in an enlarging spleen 20 …”