Hepatic Accumulation of Lysosomes and Defective Transcytotic Vesicular Pathways in Cirrhotic Rat Liver

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Abstract
: To investigate the potential role of lysosomes in cirrhosis, we analyzed the activity of lysosomal enzymes in rats exposed long–term to phenobarbital and carbon tetrachloride. The activity of lysosomal enzymes was markedly increased in the homogenate of cirrhotic livers (e.g., arylsulfatase 9 ± S.D.2 vs. 16 ± 6 nmoles · min-1 · mg-1 in control rats and cirrhotic rats, respectively; p < 0.001). The corresponding plasma levels were also increased (7 ± 1 vs. 12 ± 3 nmoles · min-1 · mg-1; p < 0.01), whereas biliary excretion was diminished (16 ± 7 vs. 7 ± 2 pmol · min-1 · gm liver-1; p < 0.05) in cirrhotic rats. Stereological quantification of lysosomes visualized cytochemically revealed an increase of pericanalicular lysosomes averaging 1.5 ± 0.4 around a canaliculus in controls and 3.7 ± 1.0 in cirrhotic rats (p < 0.01). Because this suggested a defect in the transcellular vesicular pathway, we investigated the biliary excretion of horseradish peroxidase and epidermal growth factor in perfused livers. Bile flow and total horseradish peroxidase excretion were similar in control rats and cirrhotic rats. However, the early peak of biliary horseradish peroxidase excretion — usually taken as evidence of paracellular transport — was increased in cirrhotic rats (13 ± 7 vs. 57 ± 22%; p < 0.01), whereas the second peak—reflecting the transcellular vesicular pathway(s)—was markedly reduced (87 ± 7 vs. 43 ± 22%; p < 0.001). A similar reduction in the biliary excretion of intact epidermal growth factor and of its degradation products was found. These results demonstrate an increased number of lysosomes in hepatocytes of cirrhotic livers; this appears to be the result of accumulation rather than proliferation, in view of the reduced transcellular vesicular movement of different markers into bile. (HEPATOLOGY 1992;16:997-1006.)