Non-Alcoholic Fatty Liver Disease and Nutritional Implications: Special Focus on Copper

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipids in hepatocytes, due to excessive fatty acid influx from adipose tissue, de novo hepatic lipogenesis, in addition to excessive dietary fat and carbohydrate intake. Chronic hepatic lipid overload induces mitochondrial oxidative stress and cellular damage leading the development of NAFLD into a more severe liver disease condition, non-alcoholic steato-hepatitis (NASH). In turn, this can progress to cirrhosis and hepatocellular carcinoma (HCC). Among others, copper is one of the main bio-metals required for the preponderance of the enzymes involved in physiological redox reactions, which primarily occurs during mitochondrial respiration. Thus, copper homeostasis could be considered a target point for counteracting the progression of NAFLD. Accordingly, many diseases are correlated to unbalanced copper levels and, actually, some clinical trials are examining the use of copper chelating agents. Currently, no pharmacological interventions are approved for NAFLD, but nutritional and lifestyle modifications are always recommended. Fittingly, antioxidant food agents recognized to improve NAFLD and its complications have been described in the literature to bind copper. Therefore, this review describes the role of nutrition in the development and progression of NAFLD with a particular focus on copper and copper-binding antioxidant compounds against NAFLD.

Keywords: NAFLD; ROS; antioxidants; copper; lipids; liver; nutrients.

Figure 1

Copper absorption, distribution, and metabolism: copper enters the enterocytes through CTR1 and flows out in the portal circulation by ATP7A. In the liver, Cu has a key role in defense against ROS (binds SOD) and in mitochondrial respiration. Linked to CP, copper is brought in the bloodstream to be transported to other tissues and organs. ATP7B ensures copper transport across the membranes of cellular organelles or allows for excess copper to be excreted into the bile. Cu: copper; CTR1: copper transporter protein-1; CCS: copper chaperone of superoxide dismutase; COX: cytochrome-C oxidase; Sco1, Sco2: cytochrome c oxidase assembly factors; Cu/Zn SOD: copper-zinc-dependent superoxide dismutase; ATP7A/B: copper-transporting ATPase A/B.

Figure 2

Summary of the main information on the onset and progression of NAFLD linked to diet. This highlights the role of FAs and their saturation rate, as well as fructose, which is typically found in the Western diet in increasing lipogenesis and reducing FA β-oxidation, which causes oxidative stress and eventually NAFLD. These conditions are characterized by an imbalance of copper. Some natural antioxidant compounds, which bind copper, are able to counteract NAFLD. PUFA: poly-unsaturated fatty acids.