Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock

Abstract

The nisms by which these metabolic disturbaes occur are not fully understood; however, several factors have been identified which are able to mimic the effects of cachexia ecperimentally. In generaL inflammatory cytokines have been shown to play a major role in the alterations in metabolism seen in these disease states. Tumour necrosis factor-a (TNFa), interleukin-1 (IL-10), interleukin-6 (IL-6) and interferons-a and -7 have all been shown to increase hepatic lipogenesis and serm triglyceride levels (Feingold and GrunfeKl, 1987;Grunfeld et al., 1988Grunfeld et al., , 1991Darling et al., 1990;Feingold et al., 1991; Blackham et al., 1992; Ettinger et al., 1992;Furlong et al., 1992;Arias-Diaz et al., 1993;Memon et al., 1993; Stassman et al., 1993), and in some cases reduce triglyceride ckarance (Beutler et al., 1985;Noguchi et al., 1991). Antibodies to these cytokines have been shown to ameliorate the effects on lipid metabolism when sepsis is experimentally induced by injection of lipopolysaccharide (LPS) in animals (Tracey et al., 1987;Memon et al., 1993; Strassman et al., 1993), and in cachexiainducing tumour models (Sherry et al., 1989; Lgstein et al., 1991), demonstrating that alterations in lipid metabolism as a result of diwase are ideed mediated at least in part by inflammatory cytokines. Further, circulating wles of cytokines have been demonstrated to be elevated in AIDS (Gunfeld and Feingol 1992a,b), some forms of cancer (Balkwill et al., 1987;Jablons et al., 1989;Stovroff et al., 1989) and sepsis (Fong et al., 1990) al., 1990), and inhibitors of the synthesis of prostaglandin and platelet-activating factor (Welbourn and Young, 1992) but none has been completely successful in altering metabolc imbalances or increasng survival. Because of the well-known role of L-carmtie as a carrier of long-chain fatty acids into the mitochondrial matrix for oxidation (for review, see Bremer, 1983), it has recently been hypotheised that administration of carnitine to septic or cachectic patients could increase the rate of oxidation of fatty acids and normalise lid metabolism. Carnitine administration has been shown to rele the symptoms of carniine-deficient humans (Worthley et al., 1983) and increase the survival of endotoxic rats (Takeyama et al., 1989). This laboratory recently demonstrated that carnitine administration to LPS-injected rats increased survival and food consumption, and decreased plasma triglycerides and hepatic lipogenesis (Gabo et al., 1993). Mehanisms of carnitie effects in sepsis are still unknown, as in vitro rates of oxidation in isolated mitochondria from livers of LPS-injected rats were not increased by in vivo administration of carnitine.In the studies presented in this paper, we investigated whether carnitine had an effect on the level of inflammatory cytokines which are generally increased in sepsis and cachexia and are known to affect lipid metabolism. We uilised both an LPS-induced model of septic shock in rats (Takeyama et al., 1989;Gallo et al., 1993) and a rat methykholanthreneind...

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