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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #261146

Title: High fructose feeding induces copper deficiency in Sprague-Dawley rats: A novel mechanism for obesity related fatty liver

item SONG, MING - University Of Louisville
item SCHUSCHKE, DALE - University Of Louisville
item ZHOU, ZHANXIANG - University Of North Carolina
item CHEN, THERESA - University Of Louisville
item WANG, RENWEI - University Of Minnesota
item Johnson, William
item MCCLAIN, CRAIG - University Of Louisville

Submitted to: Hepatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/28/2011
Publication Date: 2/1/2012
Citation: Song, M., Schuschke, D.A., Zhou, Z., Chen, T., Wang, R., Johnson, W.T., Mcclain, C.J. 2012. High fructose feeding induces copper deficiency in Sprague-Dawley rats: A novel mechanism for obesity related fatty liver. Hepatology. 56:433-440.

Interpretive Summary: The incidence of obesity has risen over the last three decades in the United States and worldwide, and has become a major public health concern because obesity often leads to heart disease, high blood pressure, and diabetes. Abnormalities in fat and carbohydrate metabolism are likely to contribute to the development of diseases associated with obesity. Furthermore, the intakes of certain nutrients may influence the metabolic abnormalities that contribute to obesity associated diseases. For instance, the increase in obesity has been paralleled by an increase in fructose consumption. It has also been recognized that typical Western diets can lead to marginal intakes of copper. The results of the present study indicate that the combination of fructose intake and marginal copper deficiency interact in a manner that potentiates the development of nonalchoholic fatty liver disease in laboratory rats. Dietary fructose decreased the absorption of copper. Because copper intake was marginal, the decrease in copper absorption caused by dietary fructose caused a severe drop in liver copper content that led to impaired fat metabolism and high iron content in the liver. The resulting combination of impaired fat metabolism and high liver iron concentration caused accumulation of fat in the liver and liver damage. Thus, marginal copper intake, which is not uncommon, may contribute to the development of fatty liver disease when dietary carbohydrate intake contains a high percentage of fructose, which is common in typical modern diets.

Technical Abstract: Dietary copper deficiency is associated with a variety of manifestations of the metabolic syndrome, including hyperlipidemia and fatty liver. Fructose feeding has been reported to exacerbate complications of copper deficiency. In this study, we investigated whether copper deficiency plays a role in fructose-induced fatty liver and explored the potential underlying mechanism(s). Male weanling Sprague-Dawley rats were fed either an adequate copper or a marginally copper deficient diet for 4 weeks. Deionized water or deionized water containing 30% fructose (w/v) was also given ad lib. Both marginal copper deficiency and fructose feeding led to hepatic steatosis. However, dietary fructose and marginal copper deficiency synergistically induced hepatic injury and inflammation, and accelerated fat accumulation as evidenced by robust increased plasma aspartate aminotransferase (AST), monocyte chemoattractant protein-1(MCP-1) and hepatic triglyceride. Importantly, fructose feeding further impaired copper status and led to iron overload. Copper deficiency also suppressed the hepatic antioxidant defense systems. Marginal copper deficiency induced fatty liver was characterized by microvesicular steatosis. Reduced hepatic carnitine palmitoyl-CoA transferase I (CPT I) expression, together with microvesicular steatosis suggested that impaired mitochondrial fatty acid ß-oxidation plays a role in copper deficiency and fructose feeding induced fatty liver. Up-regulated hepatic fatty acid synthase in copper deficiency indicated that increased de novo lipogenesis also contributes to copper deficiency induced fatty liver. Furthermore, marginal copper deficiency induced copper transporter 1 (Ctr1) accumulation in the duodenal epithelium was blocked by fructose feeding. Conclusion: Our data suggest that high fructose-induced nonalcoholic fatty liver disease (NAFLD) may be due, in part, to inadequate dietary copper. Impaired intestinal epithelium Ctr1 seen in fructose feeding may lead to decreased copper absorption, and subsequent copper deficiency.