Hyperlipemia: a role in regulating UCP3 gene expression in skeletal muscle during cancer cachexia?

Abstract

Rats bearing the Yoshida AH-130 ascites hepatoma showed an increased expression of both uncoupling protein-2 (UCP2) (two-fold) and UCP3 (three-to four-fold) in skeletal muscle (both soleus and gastrocnemius). The increase in mRNA content was associated with increased circulating concentrations of fatty acids (two-fold), triglyceride (two-fold) and cholesterol (1.9-fold). Administration of nicotinic acid to tumor-bearing rats abolishes the hyperlipidemic increase associated with tumor burden. The vitamin treatment also resulted in a decreased UCP3 gene expression in soleus muscle but not in gastrocnemius. It is concluded that circulating fatty acids may be involved in the regulation of UCP3 gene expression in aerobic muscles during experimental cancer cachexia. Since the UCP3 protein could have a role in energy expenditure, it may be suggested that hypolipidemic agents may have a beneficial role in the treatment of the cachectic syndrome. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Activation of UCPs gene expression in skeletal muscle can be independent on both circulating fatty acids and food intake

“…In previous work carried out in our laboratory, using the Yoshida AH-130 ascites hepatoma as a cachexia model in the rat, we have reported that both UCP2 and UCP3 gene expressions are increased in skeletal muscle [19], and that TNF seems to be partly responsible for the activation of the transcription of the two genes [38] via an increased FFA plasma concentration [20]. Thus, we have shown that the administration of nicotinic acid (a hypolipidemic agent) resulted in a downregulation of the UCP3 gene in soleus muscle, while no changes were observed concerning UCP2 mRNA content, suggesting a differential regulation of the UCP3 gene versus the UCP2 one, since only the former responded to variation in circulating FFA levels [20]. The results presented here question the fact that increased UCP3 gene expression in skeletal muscle is invariably associated with an elevation of circulating FFA, as mentioned before.…”

“…In fact, it has been speculated that UCP3 could have a role in lipid metabolism, possibly as a mitochondrial fatty acid carrier [35], although some controversy still exists [36]. On these lines, different experiments have shown that when the circulating FFA concentration is decreased, by means of hypolipidemic agents, the induction in both UCP2 and UCP3 is abolished [10,20]. In addition, the presence of fatty acids in C2C12 myotube cultures results in an increase in UCP3 gene expression [37].…”

Mechanisms of Cancer Cachexia

“…The mechanism for the increase in levels in skeletal muscle is complex. In a rat model of cachexia, the increase in UCP was associated with a twofold increase in circulatory fatty acid, and reduction of hyperlipidemia with nicotinic acid also reduced UCP3 expression in soleus but not in gastrocnemius muscles (31). However, in a murine model of cachexia, the increased UCP2 and UCP3 gene expression in skeletal muscle was not linked to a rise in circulatory fatty acids (30).…”

Cachexia: a problem of energetic inefficiency

“…Thus, systemic administration of TNF to rats results in an increase in both UCP2 and UCP3 gene expression in skeletal muscle [12]. This does not seem to be the result of a direct effect of the cytokine but rather seems to be associated with the hyperlipemia induced by TNF administration [47]. In fact, Masaki et al have demonstrated that TNF regulates the in vivo expression of the UCP family differentially and tissue dependently [48].…”