Human growth hormone (GH) has been shown to improve nitrogen balance in surgical patients and to decrease urea production. This has been thought to be due primarily to an increase in protein synthesis in skeletal muscle. Little attention has focused on the liver as a possible site where GH may modulate amino acid uptake and thereby divert nitrogen away from ureagenesis. The authors hypothesized that GH regulates amino acid transport in hepatocytes at the plasma membrane level. They studied hepatic amino acid transport in 20 healthy surgical patients that received saline, low-dose GH (0.1 mg/kg/day), or high-dose (0.2 mg/kg/day) GH for 3 days before operation. At operation, a 5- to 10-g wedge biopsy of the liver was obtained, and hepatocyte plasma membrane vesicles were prepared by Percoll density gradient centrifugation. Vesicle transport of [3H]-MeAIB, a highly selective system A substrate, and [3H]-glutamine, a selective system N substrate, was measured, employing a rapid mixing/filtration technique. Hepatocyte plasma membrane vesicles were also prepared from 14 rats treated with saline or one of three different GH treatment regimens: (A) 12 hours after chronic GH treatment (6 mg/kg every 12 hours x 4 doses); (B) 4 hours after acute (1 dose) GH treatment; and (C) 4 hours after chronic GH treatment. In human liver vesicles, low-dose GH resulted in a 13% decrease in system A activity (p = not significant), whereas high-dose GH caused a marked 79% decrease (6.7 ± 1.7 pmol/mg protein/10 seconds in control patients versus 1.4 ± 0.7 in GH, p < 0.05). System N was unaffected. Kinetic analysis of MeAIB transport by vesicles from high-dose GH patients showed the reduction in transport to be due to a 63% decrease in the V(max) (maximal transport velocity) with no alteration in the transport Km (carrier affinity). Vesicles from rats treated chronically with GH using a protocol similar to that used for human subjects exhibited decreased system A transport activity (10.4 ± 0.4 pmol/mg pro/10 seconds in controls versus 7.5 ± 0.2 in GH, p < 0.05) secondary to a 59% reduction in the transport V(max). Chronic growth hormone treatment decreases the activity of system A in both human and rat hepatocytes. This may be one mechanism by which GH diminishes hepatic ureagenesis and spares amino acids for peripheral protein synthesis.
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