The regulation of fatty acid and branched-chain amino acid oxidation in cancer cachectic rats: A proposed role for a cytokine, eicosanoid, and hormone trilogy

Abstract

Some postulates of a hypothesis (Fig. 1) concerned with the deregulation of muscle turnover by the hypoketonemia of cachectic tumor-bearing rats were examined. Plasma concentrations of ketone bodies ( d-(3)-hydroxybutyrate + acetoacetate) in rats bearing the Walker 256 carcinosarcoma were reduced by 45% ( P < 0.001) whereas the concentrations of triglyceride and free fatty acids were elevated by 223% ( P < 0.001) and 335% ( P < 0.001), respectively. Parallel with the changes in plasma, the livers of tumor-bearing animals showed decreased concentrations of KB by 35% ( P < 0.05) and increased concentrations of TG and FFA by 49% (NS) and 15% (NS), respectively. In comparison with values for the control liver (fed ad libitum), the perfused liver of animals bearing the Walker 256 tumor formed 42% ( P < 0.05) and 75% ( P < 0.05) less ketone bodies and CO 2, respectively, from oleate, while TG formation was enhanced by 33% ( P < 0.001). There was two- to threefold ( P < 0.001) enhancement of [1- 14C]leucine oxidation in vivo by the tumor-bearing animals. The activities of branched-chain amino acid aminotransferase and branched-chain keto acid dehydrogenase were elevated by 70% ( P < 0.001) and 560% ( P < 0.001) respectively in the gastrocnemius muscle of the tumor-bearing animals. The results of the investigation supported a second proposal of the hypothesis, namely, that cancer-induced cachexia resulted in the notable elevation in the concentration of arginine vasopressin that was accompanied by parallel increases in the plasma, urine, and muscle concentrations of prostaglandin E 2. The proposals of the original hypothesis have been augmented (Fig. 5) to include roles for PGE 2 and the cytokine cachectin/tumor necrosis factor which may engineer all of the events depicted in the original hypothesis.