Evidence suggests that the overconsumption of added sugars can induce fatty liver disease and insulin resistance.
To propose a hypothesis that added sugars induce copper deficiency which can lead to hepatic iron overload, fatty liver disease, insulin resistance and eventually non-alcoholic steatohepatitis.
On average, the intake of added sugars in humans is higher than levels that have been found to impair copper status in animals.
Narrative review.
Fructose-induced copper deficiency may be a leading cause of fatty liver disease and insulin resistance.
The reduction in the intake of added sugars may improve copper status and reduce the risk of fatty liver disease and insulin resistance.
The Western diet may be inadequate in copper with at least 25% of adults (but up to 80% or more) in the West consuming less than the estimated average requirement.
The prevalence of NAFLD has been increasing across the globe, and more so in developed nations with the incidence estimated to be about 20% of the United States adult population, but up to 30% of the general population in other Western countries.
The overconsumption of sugar may be one of the biggest drivers of NAFLD.
In a rat model of NAFLD, dietary sucrose and copper deficiency increased inflammation, fibrosis and lipogenesis.
The fructose component of dietary sucrose, in particular, can induce copper deficiency. In rats, a diet of only 3% fructose from beverage intake – a rather modest fructose consumption that is lower than typical intake of Americans – impaired copper status and led to a significant induction of hepatic injury, iron overload and fat accumulation.
The feeding of fructose in rodents, in addition to inducing low copper status and hepatic copper deficiency, leads to a number of pathologies associated with low copper. These pathologies include iron overload, increased liver enzymes (aspartate aminotransferase or AST), increased hepatic triglycerides and increased hepatic fatty acid synthase.
Perturbations in hepatic iron are seen frequently in NAFLD. Patients with NAFLD have lower hepatic copper, and those with lower levels of both hepatic copper and serum copper, have higher ferritin levels (606 mg/L vs. 224 mg/L, a 2.7-fold difference), higher hepatic iron concentrations (1184 µg/g vs. 320 µg/g, 3.7-fold higher), lower concentrations of ceruloplasmin and decreased liver gene expression for ferroportin, the cellular iron exporter.
High-fructose-induced copper deficiency in rats can also induce oxidative damage in the liver that does not appear to be wholly iron dependent, indicating some other cause of free-radical damage possibly via lower ceruloplasmin concentrations.
How high dietary fructose leads to copper deficiency and liver damage.
Another strategy for lowering iron levels, besides increasing copper status, is phlebotomy which can significantly treat NAFLD by improving insulin resistance.
Although copper deficiency can lead to glucose intolerance, this phenomenon appears to occur only with simultaneous feeding of glucose or fructose, but not with starch.
Feeding of isolated cholesterol in animals can also induce copper deficiency, and in turn, deficiency of copper can induce hypercholesterolemia as well as glucose intolerance and hypertriglyceridemia.
Copper deficiency may play an important, if not the major, part in the promotion of NAFLD, insulin resistance and atherosclerosis. Known risk factors for heart disease which can be induced by copper deficiency, include elevated triglycerides, hypertension and glucose intolerance, all of which are common in the American population. High consumption of fructose leading to copper deficiency or diets inadequate in copper, could be the ‘missing link’ in NAFLD, insulin resistance and IHD, one that would be easily remedied by better food choices (such as shellfish, organ meats, oysters, nuts, seeds and beans) or even merely a copper supplement.
The Western diet is loaded with fructose via the consumption of added sugars. Recent estimates put sugar consumption at 15% – 30% of calories consumed with 13% of the population consuming at least 25% of their calories from added
The Western world is currently in the throes of an epidemic of obesity and diabetes, and along with it, fatty liver. The rest of the world is catching up in incidence of these diseases. Fructose, via the induction of copper deficiency, could be driving these conditions, along with the well-known and long-standing epidemic of heart disease. The evidence presented here shows that high sugar consumption with resultant copper deficiency could well be a very important factor in these diseases of civilisation. More research is needed to (1) to delineate the degree to which the average person is copper sufficient or insufficient; (2) study the degree to which groups of people with or without these diseases differ in levels of body copper stores and dietary copper intake; (3) study trials of copper supplementation and/or prospective studies of copper status and ensuing pathologies; and (4) explain mechanisms of fructose-induced copper deficiency and iron overload.
The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.
J.J.D. performed the literature search. All authors contributed to edits and to the writing of the article.