Inhibition of system A amino acid transport and hepatocyte proliferation following partial hepatectomy in the rat.
System A, the sodium-dependent neutral amino acid transport activity, has a 3-fold increase in its initial uptake velocity into hepatocytes following partial hepatectomy (PH) in the rat. The purpose of this study was to examine the effect of inhibition of System A-mediated amino acid transport on hepatocyte proliferation and liver regeneration. We describe the in vivo competitive inhibition of System A activity following PH by the nonmetabolizable, System A-specific substrate, alpha-(methylamino)isobutyric acid (MeAIB). Administration of MeAIB 60 minutes before PH decreased the incorporation of [(3)H]thymidine into DNA by 45% +/- 5% and 76% +/- 17% at 24 and 36 hours, respectively. The readministration of MeAIB every 12 hours further decreased DNA synthesis by 92% +/- 18% and 82% +/- 11% at 24 and 36 hours. The recovery of liver mass of rats receiving MeAIB was decreased by 46.4% +/- 5.1% at 24 hours after PH. In vitro, 5 mmol/L MeAIB inhibited proliferation of primary hepatocytes by 56% +/- 4% and 61% +/- 12% 48 hours after incubation with 10% fetal calf serum or epidermal growth factor (5 ng/mL), respectively. Thus, MeAIB inhibition of System A transport activity decreased both in vivo and in vitro inducement of hepatocyte proliferation. Treatment with MeAIB did not significantly change the incorporation of [(3)H]leucine into total liver protein, but changes in serum amino acids and hepatocyte cell volume were observed, suggesting System A transport activity during hepatocyte proliferation functions primarily to provide amino acids to fuel liver-specific biochemical pathways and to increase cell volume.
Freeman
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Departments of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
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Mailliard
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D000409:Alanine / Q000494:pharmacology; D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001622:Betaine / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D006498:Hepatectomy; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D002352:Carrier Proteins; D018809:Proliferating Cell Nuclear Antigen; D015091:beta-Alanine; C012924:2,2-dimethyl-beta-alanine; D001622:Betaine; D004247:DNA; D000409:Alanine