Dietary Iron Overload and Induced Lipid Peroxidation Are Associated With Impaired Plasma Lipid Transport and Hepatic Sterol Metabolism in Rats

Abstract

Although hemochromatosis is characterized by dramatic morphological and functional alterations in the liver, little is known about the effects of an excess of iron on lipid metabolism. Therefore, we determined the effect of chronic iron overload on plasma lipid profile and lipoprotein composition, as well as on hepatic cholesterol metabolism and biliary sterol output. Rats administered a diet enriched with 3% iron carbonyl for 12 weeks displayed a 30-fold increase in iron (P F .0001) and a 5-fold rise in malondialdehyde (P F .001) in the liver. When compared with pair-fed controls, iron-overload rats showed a significant increase in triglycerides (P F .005), free cholesterol (P F .006), cholesteryl ester (P F .007), and high-density lipoprotein (HDL)-cholesterol (P F .003). Triglyceride and cholesteryl ester enrichment, protein depletion, size increase, and apolipoprotein composition alterations characterized the very low density lipoprotein (VLDL) and HDL particles of iron-overload rats. Assessment of the activity of intracellular key enzymes for cholesterol homeostasis in these rats disclosed a reduction in 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase (66%, P F .005) and cholesterol 7␣-hydroxylase (58%, P F .0004) with an increment of acyl-CoA: cholesterol acyltransferase (62%, P F .002). The lack of optimal enzymatic activity may be a result of marked membrane lipid peroxidation that brings about fluidity drop (P F .

Inflammatory reaction without endogenous antioxidant response in Caco-2 cells exposed to iron/ascorbate-mediated lipid peroxidation

“…Caco-2 cells were cultured in the presence or absence of Fe 2ϩ /ascorbate (0.2:2 mM; Sigma, St. Louis, MO) for periods varying between 1 and 24 h. The amount of free malondialdehyde (MDA) formed during the reaction was determined by HPLC, as we previously described (6). Proteins were first precipitated with a 10% sodium tungstate (Na 2WO4) solution (Aldrich, Milwaukee, WI).…”

“…Given this mounting evidence for prooxidant role of ascorbate in the presence of redoxactive transition metal ions, we previously used the Fe 2ϩ / ascorbate system to investigate the repercussions of lipid peroxidation on lipid metabolism. We found that iron/ascorbate-induced peroxidation provoked profound perturbations in lipid transport, apoprotein biogenesis, lipoprotein assembly, and sterol regulatory enzymes, which play a critical role in cholesterol homeostasis (6,7,9).…”

“…These cells are not only responsible for nutrient transport, but also actively participate in local epithelial immune response, which can enhance protection against microbial and dietary antigens (15). With regards to the daily challenge by various diet-derived oxidants, the intestine is endowed with several defense mechanisms that preserve cellular integrity and tissue homeostasis (5,6,10,14,15,21,42). It has become increasingly apparent that patients with Crohn's disease exhibit elevated free radical levels and an improper antioxidant defense system (20,25,29,39,51,54).…”

Sobrecarga de ferro em ratos sadios

“…Em estudo anterior do nosso laboratório, demonstrou-se aumento significativo da concentração de Fe no fígado (cerca de 12,2 % em relação ao grupo controle) após 90 dias de consumo de rações com moderada sobrecarga de Fe (550 mg/kg) (COCATO, 2008). Outros estudos demonstraram aumento da concentração hepática de Fe proporcional à concentração na ração em intervalo variando de 3 mg a 1500 mg de Fe/kg de ração (WARD et al, 1991;DABBAGH et al, 1994;BRUNET et al, 1999;WHITTAKER e CHANDERBHAN, 2001;COCKELL et al, 2005. As análises histológicas para se avaliar a distribuição do depósito (DABBAGH et al, 1994;BRUNET et al, 1999;WHITTAKER, CHANDERBHAN, 2001;LAFAY et al, 2005). No entanto, nas condições experimentais do presente estudo, não foram observadas alterações nas transaminases e no perfil lipídico sérico bem como no perfil de ácidos graxos no fígado, sugerindo uma eventual proteção antioxidante nesse compartimento (Tabelas 4 e 8).…”

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

“…The mutation of the HFE gene leading to hereditary haemochromatosis has been one factor which has been implicated in NAFLD disease progression (6,119,121) and iron overload has been associated with oxidative stress and altered lipid and glucose metabolism (259). Previous studies from our laboratory have shown increased disease severity -steatohepatitis and necroinflammation -in Hfe knockout mice fed a high calorie diet.…”