**3. Functional interactions between copper, lipid, and other nutrients**

The Role of Copper as a Modifier of Lipid Metabolism 47

indicated that when diets with fructose, glucose or starch were combined with copper deficiency, both glucose and fructose raised plasma cholesterol levels. However, severity of copper deficiency and mortality were much greater with fructose as opposed to glucose feeding (65), suggesting that the exacerbation of copper deficiency by sucrose was due to the fructose component. More recent work (66) indicates that the effect of fructose may be at the level of absorption, whereby copper deficiency induces upregulation of the copper

Dietary fructose consumption and dietary copper deficiency independently alter fatty-acid metabolism; in combination, the effect is enhanced (66-69). Feeding weanling rats for three weeks on a diet adequate or deficient in copper along with either fructose or corn starch as a carbohydrate source (62% carbohydrate) revealed that fructose feeding enhanced indicators of copper deficiency, such as enhanced heart/body weight ratio and reduced hepatic copper (70). Analysis of hepatic enzymes involved in the lipid and carbohydrate metabolism also indicated that a diet deficient in copper had greatest metabolic effects in combination with fructose, less with glucose and least with starch (71). Glucose-6-phosphate dehydrogenase, malic enzyme, L-alpha-glycerophosphate dehydrogenase and fructose 1-6-diphosphatase were all unaffected by Cu deficiency, but their activities were enhanced most in combination with fructose, suggesting a complementary rather than direct role for fructose in

Copper deficiency in combination with fructose feeding alters the fatty acid composition of triacylglycerol in the heart and the liver. Cardiac phosphatidylinositol and phosphatidylserine were shown to increase nearly two-fold and arachidonic acid and docosapentaenoic acid to be elevated more than two-fold in copper deficient, fructose fed animals (70). A change in cardiac phospholipids may explain the increased mortality observed in copper deficient/fructose fed rats and suggest a potentially significant role for these dietary factors in ischemic heart disease. However, the observed changes in the lipid composition could not be correlated with the extent of copper deficiency, illustrating once again that a detailed mechanistic understanding of these dietary interactions could be highly

Western diet is characterized by high fructose and high fat. In combination with a likely mild copper deficiency (see above), it stands to reason that these factors may all interact to induce changes in whole body metabolism, especially lipid metabolism, producing deleterious hepatic and cardiovascular effects. When this idea is tested in rats by combining high fat and fructose, or low fat and fructose with copper deficiency, liver metabolism is most significantly affected by the fat and fructose combination (28). Sugars mobilize copper from the liver to other tissues (64), possibly causing a change in liver physiology. Recent work also indicates that the mobilization of copper from the liver may be driven by heartspecific copper deficiency (10). Thus, in addition to interaction during absorption, an important inter-organ communication exists that jointly modulates levels of copper and

transporter Ctr1, but this effect is eliminated by high fructose feeding (Figure 1).

exacerbating copper deficiency (71).

beneficial.

lipids in various tissues
