Excessive nitric oxide production does not account for the
inhibition of hepatic gluconeogenesis in endotoxemia.
Ou, Junhai, Luis Molina, Young-Myeong Kim, Timothy R. Billiar.
Department of Surgery, University of Pittsburgh, Pittsburgh PA
15261, GLAXO-WELLCOME Co., Research Triangle Park NC 27709
APStracts 3:0089G, 1996.
The pattern of inhibition of gluconeogenesis in hepatocytes was
compared between endotoxemia in vivo and NO exposure in vitro. Fasted
rats were injected with LPS (12 mg/kg) or with vehicle alone. After
2-24 hours, hepatocytes were isolated, placed in suspension, and
incubated for 1 hour with various gluconeogenic substrates that enter
at different sites of the gluconeogenic pathway. Hepatocytes from
LPS-treated rats exhibited up to a 50% decrease in gluconeogenesis
for substrates that enter proximal to GAPDH beginning at 6 hours,
followed by a nadir at 12 hours after LPS. Although hepatocytes
exposed to exogenous NO (SNAP) also exhibited a depressed
gluconeogenesis, the pattern was not the same with inhibition in
gluconeogenesis for substrates that enter the pathway both before and
after GAPDH. Furthermore, when rats injected with LPS were subjected
to a constant portal infusion (Alzet pump) of the NO synthase
inhibitors, L-NMA or aminoguanidine, no changes in the LPS-induced
gluconeogenesis suppression were seen. In addition, no difference in
LPS-induced inhibition of gluconeogenesis was detected when
hepatocytes from inducible NO synthase (NOS-2) knockout mice were
compared to cells obtained from wild type mice. Minimal decreases in
GAPDH activity were measured in hepatocytes from the LPS-treated rats
while the activity of phosphoenolpyruvate carboxykinase (PEPCK)
declined up to 40%, independent of NO synthesis. These data indicate
that NO does not account for the inhibition of gluconeogenesis in
endotoxemia and provide support for NO-independent reduction in PEPCK
activity as a more plausible explanation.
Received 8 August 1995; accepted in final form 11 April 1996.
APS Manuscript Number G341-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 May 96