In rats injected with bacterial
lipopolysaccharide (LPS; 5 gamma mg/g
body weight [BWT]), the toxin provokes death within 24 h in 23% of the animals and, in surviving rats, causes a decrease in BWT, hyperlactacidemia, hyperlipacidemia, and hyperketonemia, as well as depletion of both liver and muscle
glycogen content. In the liver, LPS severely lowers the
ATP and total
adenine nucleotide content,
ATP/
ADP ratio, and adenylate charge. In hepatocytes from LPS-injected rats, the oxidation of
D-glucose is first increased 2 h after administration of the toxin, despite close-to-normal phosphorylation of the
hexose. In hepatocytes prepared from rats killed 24 h after injection of LPS, the phosphorylation of
D-glucose, its incorporation into
glycogen, and its oxidation are all severely impaired. This sequence of changes, which coincides with a decreased ratio between
pyruvate and
lactate production from exogenous
D-glucose, is comparable to that found with agents that uncouple oxidative phosphorylation. The injection of LPS also alters the metabolic response of hepatocytes to the dimethyl
ester of
succinic acid (SAD), in terms, for instance, of the sparing action of the
ester upon both the production of 14CO2 by hepatocytes prelabeled with L-[U-14C]
glutamine and the output of NH4+, and its inhibitory action on glycogenolysis and futile cycling in the reactions catalyzed by
glucokinase and
glucose-6-phosphatase. Nevertheless, the infusion of SAD protects the rats against the deleterious effect of LPS upon such variables as the plasma concentration of
free fatty acids and
beta-hydroxybutyrate, the liver
ATP content, and the oxidation of
D-glucose, as well as the
pyruvate/
lactate ratio, in hepatocytes prepared from the LPS-injected rats. The infusion of SAD also virtually suppresses lethality in the LPS-injected animals. It is proposed, therefore, that the infusion of
succinic acid esters may represent a novel therapeutic approach in
endotoxemia and
multiple-organ failure.