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

J Hepatol. 2012 Feb;56(2):433-40. doi: 10.1016/j.jhep.2011.05.030. Epub 2011 Jul 23.


Background & aims: 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).

Methods: 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. Copper and iron status, hepatic injury and steatosis, and duodenum copper transporter-1 (Ctr-1) were assessed.

Results: Fructose feeding further impaired copper status and led to iron overload. Liver injury and fat accumulation were significantly induced in marginal copper deficient rats exposed to fructose as evidenced by robustly increased plasma aspartate aminotransferase (AST) and hepatic triglyceride. Hepatic carnitine palmitoyl-CoA transferase I (CPT I) expression was significantly inhibited, whereas hepatic fatty acid synthase (FAS) was markedly up-regulated in marginal copper deficient rats fed with fructose. Hepatic antioxidant defense system was suppressed and lipid peroxidation was increased by marginal copper deficiency and fructose feeding. Moreover, duodenum Ctr-1 expression was significantly increased by marginal copper deficiency, whereas this increase was abrogated by fructose feeding.

Conclusions: Our data suggest that high fructose-induced nonalcoholic fatty liver disease (NAFLD) may be due, in part, to inadequate dietary copper. Impaired duodenum Ctr-1 expression seen in fructose feeding may lead to decreased copper absorption, and subsequent copper deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Cation Transport Proteins / metabolism
  • Copper / administration & dosage
  • Copper / deficiency*
  • Copper Transporter 1
  • Disease Models, Animal
  • Fatty Acids / metabolism
  • Fatty Liver / etiology*
  • Fatty Liver / metabolism*
  • Fructose / administration & dosage*
  • Fructose / adverse effects
  • Iron Overload / etiology
  • Iron Overload / metabolism
  • Lipogenesis
  • Liver / injuries
  • Liver / metabolism
  • Male
  • Non-alcoholic Fatty Liver Disease
  • Obesity / complications*
  • Obesity / metabolism*
  • Oxidative Stress
  • Rats
  • Rats, Sprague-Dawley
  • Sweetening Agents / administration & dosage
  • Sweetening Agents / adverse effects


  • Cation Transport Proteins
  • Copper Transporter 1
  • Fatty Acids
  • Slc31a1 protein, rat
  • Sweetening Agents
  • Fructose
  • Copper
  • Aspartate Aminotransferases
  • Alanine Transaminase