Inhibition of system A amino acid transport and hepatocyte proliferation following partial hepatectomy in the rat
Inhibition of system A amino acid transport and hepatocyte proliferation following partial hepatectomy in the rat
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DOI：
10.1002/hep.510300212
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发表时间：
1999-08-01
期刊：
影响因子：
13.5
通讯作者：
Mailliard, ME
中科院分区：
文献类型：
--
作者：
Freeman, TL;Ngo, HQ;Mailliard, ME
系统A，钠依赖性中性氨基酸转运活性，在大鼠部分肝切除术（PH）后其进入肝细胞的初始摄取速度增加了3倍。本研究的目的是研究抑制系统A介导的氨基酸转运对肝细胞增殖和肝再生的影响。我们描述了PH后系统A活性的体内竞争性抑制作用，这种抑制作用是由非代谢的系统A特异性底物α-（甲氨基）异丁酸（MeAIB）引起的。在PH前60分钟给予MeAIB可使[H-3]胸苷在24小时和36小时分别减少45% +/- 5%和76% +/- 17%。每12小时再施用MeAIB进一步使DNA合成在24和36小时降低92% +/-18%和82% +/-11%。在体外，5 mmol/L MeAIB与10%胎牛血清或表皮生长因子（5 ng/mL）孵育48 h后，分别抑制原代肝细胞增殖56% +/- 4%和61% +/- 12%。因此，MeAIB对系统A转运活性的抑制降低了肝细胞增殖的体内和体外诱导。用MeAIB治疗没有显著改变[H-3]亮氨酸掺入总肝蛋白中，但观察到血清氨基酸和肝细胞体积的变化，表明肝细胞增殖过程中系统A转运活性主要用于提供氨基酸来为肝脏特异性生化途径提供燃料并增加细胞体积。
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 [H-3]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 [H-3]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.