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

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 < .0001) and a 5–fold rise in malondialdehyde ( P < .001) in the liver. When compared with pair–fed controls, iron–overload rats showed a significant increase in triglycerides ( P < .005), free cholesterol ( P < .006), cholesteryl ester ( P < .007), and high–density lipoprotein (HDL)–cholesterol ( P < .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 (HMG–CoA) reductase (66%, P < .005) and cholesterol 7α–hydroxylase (58%, P < .0004) with an increment of acyl–CoA: cholesterol acyltransferase (62%, P < .002). The lack of optimal enzymatic activity may be a result of marked membrane lipid peroxidation that brings about fluidity drop ( P < .029) in microsomes of iron–overload rats (5.00 ± 0.013) versus controls (8.20 ± 0.03), reflected by polarization. A decline of the pool size of cholesterol and bile acids was noted in iron–overload rats during a 6–hour bile drainage. Our results show that experimental iron overload causes marked perturbations in plasma lipid transport and hepatobiliary sterol metabolism. Given the positive correlation of malondialdehyde with most of the altered parameters, iron–catalyzed lipid peroxidation may well be one of the involved mechanisms.