**1. Introduction**

38 Lipid Metabolism

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wall. *Cardiovasc Hematol Disord Drug Tagets*. 2006, 6(1): 1-19.

#### **1.1. Copper homeostasis in mammals**

Dietary copper enters the body largely through the small intestine. Two membrane transporters are essential for this process. The high affinity copper uptake protein Ctr1 is responsible for making copper that enters via the apical membrane available in the cytosol for further utilization (1), whereas the copper-transporting ATPase ATP7A facilitates copper exit from the enterocytes into circulation (2) (Figure 1). Complete genetic inactivation of either transporter in experimental animals is embryonically lethal (3-5). However, partial inactivation or tissue specific inactivation of ATP7A or Ctr1, respectively, in either case is associated with copper accumulation in the intestine, impaired copper entry into the bloodstream, and severe copper deficiency in many organs and tissues (1). Copper deficiency, in turn, produces distinct metabolic changes that are discussed in detail in the following sections.

The majority of absorbed dietary copper is initially delivered to the liver. Hepatocytes utilize copper for their metabolic needs (such as respiration and radical defense); they also synthesize and secrete the major copper containing protein in serum, ceruloplasmin, and prevent copper overload in the body by exporting excess copper via the canalicular membrane into the bile (Figure 1). These two important functions of hepatocytes (the production of ceruloplasmin and the removal of excess copper) are performed by another transporter, the copper transporting ATPase ATP7B, which is homologous to ATP7A (6, 7). Inactivation of ATP7B in patients with Wilson's disease and in animal models is associated with marked copper overload in the liver and pathologic changes including marked lipid dysregulation in the liver and the serum (discussed in the later sections).

© 2013 Lutsenko and Burkhead, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Role of Copper as a Modifier of Lipid Metabolism 41

metabolism. Significance of these observations is becoming more and more apparent given recent data that dietary influences (such as amount of fat in the diet) could be important modifiers of the course and severity of the disorders associated with copper misbalance (11). Reciprocally, copper deficiency has emerged as a factor in the development of Non-alcoholic Fatty-Liver Disease (NAFLD)(12, 13), although current reports paint complex picture (14) and further studies are needed. Despite ample phenotypic evidence in support of copperlipid interactions, little mechanistic work has been done so far, and current understanding of this metabolic interaction at the molecular level is very limited. The goal of this review is

Copper deficiency has long been known to alter lipid metabolism; consequently, it has been proposed as a significant factor in human diseases associated with dyslipidemia (15). Copper deficiency is rarely diagnosed in humans, with a notable exception of a growing number of reports pointing to copper and other mineral insufficiencies as unintended consequences of bariatric surgeries (16-18). The under-detection of copper deficiency could be due to limitations of screening using serum or urine samples. Although liver is the main homeostatic organ for copper and has a high copper content, copper levels in serum and urine do not correlate well with a hepatic copper concentration (19), possibly masking

Recent work using a categorical regression analysis of copper deficiency and excess shows a U-shaped dose-response curve. Compilation of data on toxicity due to copper excess and deficiency yielded a generalized linear model that was used to estimate adverse responses depending on copper dose or severity of copper limitation, as well as duration of copper misbalance (20). This model indicates that for humans the optimal intake level for Cu is 2.6 mg/day. The current United States Recommended Daily Intake is only 0.9 mg (US Food and Nutrition Board), whereas dietary study indicated that even 1.03 mg of Cu/day may be insufficient for adult men (21). The results of the third National Health and Nutrition Examination Survey (NHANES III, 2003) in the US showed that the mean daily intake of copper, depending on age, was 1.54–1.7 mg*/*day (±0.05 standard deviation (SD)) for men and 1.13-1.18 mg*/*d (±0.05 SD) for women. These results imply that a large portion of the

population may have insufficient dietary copper intake and mild copper deficiency.

Current data suggest that copper deficiency may be a common contributing factor in cardiovascular disease (CVD) and non-alcoholic fatty-liver disease (NAFLD) (22-24). As described above, surgical obesity treatment has also been strongly implicated in copper deficiency, likely by causing a diminished absorption of copper after a gastric bypass surgery (16-18). In addition, low copper levels were detected in organs, plasma and tissue of

to illustrate and emphasize the need for such detailed mechanistic investigations.

**2. Copper deficiency** 

deficiency in the liver.

**2.2. Low copper and human disease** 

**2.1. Copper in western diet** 

**Figure 1. Copper homeostasis and lipid metabolism display functional interactions.** Copper enters circulation via small intestine where copper transporters Ctr1 and ATP7A play the major role in the dietary copper absorption. Dietary copper deficiency is associated with a lower level of ceruloplasmin in the serum and increase in cholesterol and lipoproteins. Copper deficiency also upregulates the copper uptake protein Ctr1 in intestine; this compensatory effects is diminished by high fructose. In the liver, copper deficiency is associated with increased synthesis of cholesterol and higher expression of fatty acid synthase (FAS). Also, in the liver, the copper-transporting ATPase ATP7B mediates copper delivery to ceruloplasmin and copper export into the bile. Genetic inactivation of ATP7B in Wilson's disease is associated with copper overload and marked changes in lipid metabolism. Cholesterol biosynthesis is downregulated and both the serum and hepatic lipid profiles are altered.

The level of expression of copper transporters and their regulation varies between various organs (8). For example, ATP7B is the main transporter in hepatocytes, but it is absent from the adrenal gland, whereas opposite is true for ATP7A (9). Most of the tissues such as heart, brain, lung, placenta and kidneys express both copper-transporting ATPases along with the two copper uptake systems Ctr1 and Ctr2. As a result, the consequences of copper deficiency and copper overload are tissue specific, and certain organs such as heart or liver are more profoundly affected (see below). Recent studies also revealed an important homeostatic cross-talk between different organs in either copper deficiency or copper overload. For example, copper overload in the liver is accompanied by functional copper deficiency in the adrenal gland (9), whereas severe copper deficiency in the heart stimulates copper efflux from the liver (10), presumably to compensate for the deleterious effects of copper depletion.

The analysis of available literature also illustrates that variations in copper levels, either through the diet or as a result of genetic copper misbalance, have a profound effect on lipid metabolism. Significance of these observations is becoming more and more apparent given recent data that dietary influences (such as amount of fat in the diet) could be important modifiers of the course and severity of the disorders associated with copper misbalance (11). Reciprocally, copper deficiency has emerged as a factor in the development of Non-alcoholic Fatty-Liver Disease (NAFLD)(12, 13), although current reports paint complex picture (14) and further studies are needed. Despite ample phenotypic evidence in support of copperlipid interactions, little mechanistic work has been done so far, and current understanding of this metabolic interaction at the molecular level is very limited. The goal of this review is to illustrate and emphasize the need for such detailed mechanistic investigations.
