Effects of Antihypertensive and Triglyceride‐lowering Agents on Hepatic Copper Concentrations in Rats with Fatty Liver Disease

Abstract

Copper deficiency had been suggested to link between fructose-enriched diet (FED) and the development of non-alcoholic fatty liver disease (NAFLD). In this study, we characterized changes in hepatic copper concentrations and hepatic oxidative milieu, in rats with the metabolic syndrome and NAFLD as a result of FED with pharmacological manipulations to reduce blood pressure or plasma triglycerides. Changes in plasma and hepatic copper concentrations were correlated with changes observed in the immunohistochemical hepatic expression of copper-zinc-superoxide dismutase (CuZnSOD; SOD1), metallothionein (MT) and nitrotyrosine (NITT). FED administration was associated with a 2.2-fold reduction in hepatic copper concentrations, a decrease in the hepatic SOD1 expression, disappearance of the hepatic MT expression and increase in the hepatic NITT expression. Bezafibrate administration restored the hepatic copper concentrations and the hepatic SOD1 expression to levels that were observed in the control rats. A significant positive correlation between hepatic copper concentrations and the values of hepatic SOD1 expression of each animal included in this study was found. Administration of either captopril or bezafibrate increased hepatic MT expression, however, to levels that were lower than those observed in the control group. Administration of either amlodipine, or captopril or bezafibrate to the FED rats, had no effect on hepatic NITT expression. NAFLD development in FED rats is associated with a decrease in hepatic copper concentrations that is associated with a decrease in the hepatic SOD1 expression. Bezafibrate administration increases hepatic copper concentrations and restores the hepatic SOD1 expression.Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. The worldwide prevalence of NAFLD continues to increase with the growing obesity epidemic (reviewed in [1]). The most common risk factor for NAFLD is the presence of the metabolic syndrome that includes abdominal obesity and two or more of the following features: high blood pressure, elevated fasting plasma glucose and triglyceride levels, or low plasma HDL cholesterol levels. NAFLD is considered to be the hepatic manifestation of the metabolic syndrome (reviewed in [2]).Accumulating evidence from human and animal studies suggests that the increasing prevalence of NAFLD is associated with the increasing intake of simple sugars, especially fructose (reviewed in [3,4]). Consumption of fructose for long periods can predispose animals and individuals to hepatic fatty infiltration and the metabolic syndrome [3][4][5][6][7]. In recent years, the consumption of fructose, which is used in the food industry as a sweetener, has tremendously increased [4].As of now, multiple pathophysiological mechanisms including copper deficiency have linked between the increased fructose consumption and the development of NAFLD [4,[8][9][10][11][12].Copper is a trace element that is essential to the function of several enzymes involved in a vari...

Distinct Phenotype of Non-Alcoholic Fatty Liver Disease in Patients With Low Levels of Free Copper and of Ceruloplasmin

“…This protein without the incorporation of six to seven copper ions is very labile and has a shorter life time (21) . This could even be one reason for the lower levels of Cu/Zn superoxide dismutase in NAFLD patients (22)(23)(24) . Indeed, low levels of cuproenzymes were described during the status of copper deficiency, especially those of ceruloplasmin (25,26) In copper-deficient rats, copper administration by oral gavage increased the rate of ceruloplasmin synthesis, in contrast to normal rats in which plasma ceruloplasmin levels were not elevated.…”

Risk factors for development of nonalcoholic fatty liver disease after pancreatoduodenectomy

“…reported that serum Cu levels were lower in patients with conventional NAFLD than in controls. Ackerman et al 21. suggested that Cu deficiency in rats was a link between a fructose‐enriched diet and the development of NAFLD.…”

Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases

“…Because the decreased antioxidant defence and functional abnormalities of mitochondria are closely related to the worsening hepatic pathology of NAFLD, hepatic COX activity and SOD1 expression were either unchanged or reduced [117,[141][142][143].…”

“…In addition, metallothionein protects hepatocytes against oxidative damage [146] . Hence, the downregulation of metallothionein might be an indicator of enhanced oxidative stress in NAFLD and NASH disorders [141,147,148].…”

“…EGCG was also described as a potent CTR1 regulator [151] . In addition to antioxidants, bezafibrate and captopril can modify the hepatic oxidative milieu by restoring hepatic copper homeostasis, metallothionein, and SOD1 expression [141] However, additional copper supply should be more careful. One clinic case series described an improvement in copper and ceruloplasmin levels, along with the recovery of liver function in two of three patients with liver diseases after receiving copper supplementation [152].…”