Inhibition of System A amino acid transport and hepatocyte proliferation following partial hepatectomy in the rat

Thomas L. Freeman, Hao Q. Ngo, Mark E Mailliard

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Abstract

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, α-(methylamino)isobutyric acid (MeAIB). Administration of MeAIB 60 minutes before PH decreased the incorporation of [3H]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 [3H]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.

Original languageEnglish (US)
Pages (from-to)437-444
Number of pages8
JournalHepatology
Volume30
Issue number2
DOIs
StatePublished - Aug 9 1999

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Amino Acid Transport Systems
Hepatectomy
Hepatocytes
Cell Size
Amino Acids
Liver
Neutral Amino Acids
Liver Regeneration
DNA
isobutyric acid
Serum
Epidermal Growth Factor
Leucine
Thymidine
Sodium

ASJC Scopus subject areas

  • Hepatology

Cite this

Inhibition of System A amino acid transport and hepatocyte proliferation following partial hepatectomy in the rat. / Freeman, Thomas L.; Ngo, Hao Q.; Mailliard, Mark E.

In: Hepatology, Vol. 30, No. 2, 09.08.1999, p. 437-444.

Research output: Contribution to journalArticle

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abstract = "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, α-(methylamino)isobutyric acid (MeAIB). Administration of MeAIB 60 minutes before PH decreased the incorporation of [3H]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 [3H]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.",
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