Myers B M, Prendergast F G, Holman R, Kuntz S M, LaRusso N F
Center for Basic Research in Digestive Diseases, Mayo Clinic, Medical School and Foundation, Rochester, Minnesota 55905.
J Clin Invest. 1991 Oct;88(4):1207-15. doi: 10.1172/JCI115423.
While hemochromatosis is characterized by sequestration of iron-protein complexes in hepatocyte lysosomes, little is known about the effects of excess iron on these organelles. Therefore, we studied the effects of experimental iron overload on hepatocyte lysosomal structure, physicochemical properties, and function in rats fed carbonyl iron. A sixfold increase (P less than 0.0001) in hepatic iron and a fivefold increase in lysosomal iron (P less than 0.01) was observed after iron loading; as a result, hepatocyte lysosomes became enlarged and misshapen. These lysosomes displayed increased (P less than 0.0001) fragility; moreover, the fluidity of lysosomal membranes isolated from livers of iron-loaded rats was decreased (P less than 0.0003) as measured by fluorescence polarization. Malondialdehyde, an end product of lipid peroxidation, was increased by 73% (P less than 0.008) in lysosomal membranes isolated from livers of iron-overloaded rats. While amounts of several individual fatty acids in isolated lysosomal membranes were altered after iron overload, cholesterol/phospholipid ratios, lipid/protein ratios, double-bond index, and total saturated and unsaturated fatty acids remained unchanged. The pH of lysosomes in hepatocytes isolated from livers of iron-loaded rats and measured by digitized video microscopy was increased (control, 4.70 +/- 0.05; iron overload, 5.21 +/- 0.10; P less than 0.01). Our results demonstrate that experimental iron overload causes marked alterations in hepatocyte lysosomal morphology, an increase in lysosomal membrane fragility, a decrease in lysosomal membrane fluidity, and an increase in intralysosomal pH. Iron-catalyzed lipid peroxidation is likely the mechanism of these structural, physicochemical, and functional disturbances.
虽然血色素沉着症的特征是铁蛋白复合物在肝细胞溶酶体中蓄积，但关于过量铁对这些细胞器的影响却知之甚少。因此，我们研究了实验性铁过载对喂食羰基铁的大鼠肝细胞溶酶体结构、物理化学性质和功能的影响。铁负荷后，肝脏铁含量增加了6倍（P<0.0001），溶酶体铁含量增加了5倍（P<0.01）；结果，肝细胞溶酶体变得肿大且形状异常。这些溶酶体的脆性增加（P<0.0001）；此外，通过荧光偏振测量，从铁负荷大鼠肝脏分离的溶酶体膜的流动性降低（P<0.0003）。脂质过氧化的终产物丙二醛在从铁过载大鼠肝脏分离的溶酶体膜中增加了73%（P<0.008）。虽然铁过载后分离的溶酶体膜中几种个别脂肪酸的含量发生了变化，但胆固醇/磷脂比率、脂质/蛋白质比率、双键指数以及总饱和脂肪酸和不饱和脂肪酸保持不变。通过数字化视频显微镜测量，从铁负荷大鼠肝脏分离的肝细胞溶酶体的pH值升高（对照，4.70±0.05；铁过载，5.21±0.10；P<0.01）。我们的结果表明，实验性铁过载导致肝细胞溶酶体形态发生明显改变，溶酶体膜脆性增加，溶酶体膜流动性降低，溶酶体内pH值升高。铁催化的脂质过氧化可能是这些结构、物理化学和功能紊乱的机制。
