Brunet S, Thibault L, Delvin E, Yotov W, Bendayan M, Levy E
Department of Nutrition, Hôpital Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
Hepatology. 1999 Jun;29(6):1809-17. doi: 10.1002/hep.510290612.
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 7alpha-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.
尽管血色素沉着症的特征是肝脏出现显著的形态和功能改变，但对于铁过量对脂质代谢的影响却知之甚少。因此，我们确定了慢性铁过载对血浆脂质谱和脂蛋白组成的影响，以及对肝脏胆固醇代谢和胆汁甾醇输出的影响。给予富含3%羰基铁的饮食12周的大鼠，肝脏中铁含量增加了30倍（P<.0001），丙二醛含量增加了5倍（P<.001）。与配对喂养的对照组相比，铁过载大鼠的甘油三酯（P<.005）、游离胆固醇（P<.006）、胆固醇酯（P<.007）和高密度脂蛋白（HDL）胆固醇（P<.003）显著增加。甘油三酯和胆固醇酯富集、蛋白质减少、颗粒大小增加以及载脂蛋白组成改变是铁过载大鼠极低密度脂蛋白（VLDL）和HDL颗粒的特征。对这些大鼠中胆固醇稳态的细胞内关键酶活性的评估显示，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶降低了66%（P<.005），胆固醇7α-羟化酶降低了58%（P<.0004），而酰基辅酶A：胆固醇酰基转移酶增加了62%（P<.002）。缺乏最佳酶活性可能是由于铁过载大鼠微粒体中明显的膜脂质过氧化导致流动性下降（P<.029）（铁过载大鼠为5.00±0.013，对照组为8.20±0.03），这通过偏振反映出来。在6小时的胆汁引流过程中，铁过载大鼠的胆固醇和胆汁酸池大小下降。我们的结果表明，实验性铁过载会导致血浆脂质转运和肝胆甾醇代谢出现明显紊乱。鉴于丙二醛与大多数改变的参数呈正相关，铁催化的脂质过氧化很可能是其中涉及的机制之一。
