Tumor necrosis factor-alpha inhibits albumin gene expression in a murine model of cachexia.

The mechanisms responsible for decreased serum albumin levels in patients with cachexia-associated infection, inflam- mation, and cancer are unknown. Since tumor necrosis factor-a (TNFa) is elevated in cachexia-associated diseases, and chronic administration of TNFa induces cachexia in animal models, we assessed the regulation of albumin gene expression by TNFa in vivo. In this animal model of cachexia, Chinese hamster ovary cells transfected with the functional gene for human TNFa were inoculated into nude mice (TNFa mice). TNFa mice became cachectic and manifested decreased serum albumin levels, albumin synthesis, and albumin mRNA levels. However, even before the TNFa mice lost weight, their albu- min mRNA steady-state levels were decreased 90%, and in situ hybridization revealed a low level of albumin gene expres- sion throughout the hepatic lobule. The mRNA levels of sev- eral other genes were unchanged. Hepatic nuclei from TNFa mice before the onset of weight loss were markedly less active in transcribing the albumin gene than hepatic nuclei from con- trol mice. Therefore, TNFa selectively inhibits the genetic ex- pression of albumin in this model before weight loss. (J. Clin. Invest. 1990. 85:248-255.) albumin * cachexia * liver tumor necrosis factor-a, transcription Introduction Serum albumin levels are decreased in patients with cachexiaassociated infection, inflammation, and cancer, and the re- duction in serum albumin levels is used clinically as an indicator of the severity of the chronic disease state (1). Serum albumin levels reflect a complex interaction between the syn- thesis, volume of distribution, degradation, and losses of this protein. The mechanisms responsible for the hypoalbumin- emia of cachexia are unknown. It has been shown that the hypoalbuminemia of chronic inflammatory diseases (2) and of chronic renal failure (3) is at least in part the result of de- creased albumin synthesis. If albumin synthesis is decreased in cachexia, then this could be either a nonspecific effect of malnutrition or the specific effect of a humoral factor inhibiting albumin synthesis.