LeHoux J G, Grondin F
Department of Biochemistry, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Endocrinology. 1993 Mar;132(3):1078-84. doi: 10.1210/endo.132.3.7679967.
Chitosan, a natural product derived from chitin, possesses hypocholesterolemic properties similar to those of cholestyramine, but there has been no report concerning its effects on the equilibrium between dietary cholesterol and de novo cholesterol synthesis in the liver. In this work, we studied the effects of chitosan on plasma and liver cholesterol levels, liver weight, and the key regulatory enzyme of cholesterogenesis 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase in rats fed a sterol diet containing 1% cholesterol and 0.2% cholic acid. The animals given the sterol diet showed increases in plasma and liver cholesterol, which were lowered by 54% in plasma and 64% in liver by 5% chitosan, while cholestyramine completely blocked such increases. HMG-CoA reductase activity was considerably increased in the sterol-cholestyramine group, but was greatly decreased in both sterol and sterol-chitosan groups. There was no change in liver weight or appearance after treatment with chitosan, but cholestyramine-treated animals manifested secondary effects from the treatment, including smaller yellowish livers. High mol wt chitosans [> 750 kilodaltons (kDa)] were found to be less effective as hypocholesterolemia than a 70-kDa preparation. Also, when the 70-kDa chitosan was used at 2.5%, 5%, and 7.5% of the total diet, its effectiveness was greatest at the higher concentrations; indeed, incorporation of 7.5% chitosan in the sterol diet for 3 weeks completely prevented any decrease in plasma high density lipoprotein cholesterol or increase in the plasma cholesterol level and liver weight. This formula greatly reduced the increase in liver cholesterol content due to the sterol diet, with values of 8.8 +/- 1.3 for the sterol-chitosan diet vs. 18.2 +/- 0.8 mg/g tissue for the sterol diet. The increased intake of sterols considerably lowered both HMG-CoA reductase activity (33-fold) and HMG-CoA reductase mRNA levels (3-fold) in rat liver, but in the sterol-chitosan group, HMG-CoA reductase activity was 7.7 times more elevated than in the sterol group, although it was still lower than the control value, whereas HMG-CoA reductase mRNA levels were normal. The results obtained did not differ significantly when rats were studied for 1, 3, or 6 weeks. These results taken collectively indicate that the 7.5% chitosan formula maintained adequate cholesterol homeostasis in rats, despite a greatly increased intake of cholesterol.
壳聚糖是一种从几丁质衍生而来的天然产物，具有与消胆胺类似的降胆固醇特性，但尚无关于其对肝脏中膳食胆固醇与从头合成胆固醇之间平衡影响的报道。在本研究中，我们研究了壳聚糖对喂食含1%胆固醇和0.2%胆酸的甾醇饮食的大鼠的血浆和肝脏胆固醇水平、肝脏重量以及胆固醇生物合成关键调节酶3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的影响。给予甾醇饮食的动物血浆和肝脏胆固醇升高，5%壳聚糖可使血浆胆固醇降低54%，肝脏胆固醇降低64%，而消胆胺可完全阻止此类升高。HMG-CoA还原酶活性在甾醇-消胆胺组中显著增加，但在甾醇组和甾醇-壳聚糖组中均大幅降低。壳聚糖处理后肝脏重量或外观无变化，但消胆胺处理的动物出现了处理的继发效应，包括较小的淡黄色肝脏。发现高分子量壳聚糖[>750千道尔顿（kDa）]作为降胆固醇药物的效果不如70-kDa制剂。此外，当70-kDa壳聚糖以总饮食的2.5%、5%和7.5%使用时，其在较高浓度下效果最佳；实际上，在甾醇饮食中加入7.5%壳聚糖3周可完全防止血浆高密度脂蛋白胆固醇降低或血浆胆固醇水平和肝脏重量增加。该配方极大地降低了由于甾醇饮食导致的肝脏胆固醇含量增加，甾醇-壳聚糖饮食的值为8.8±1.3，而甾醇饮食为18.2±0.8mg/g组织。甾醇摄入量的增加显著降低了大鼠肝脏中HMG-CoA还原酶活性（33倍）和HMG-CoA还原酶mRNA水平（3倍），但在甾醇-壳聚糖组中，HMG-CoA还原酶活性比甾醇组高7.7倍，尽管仍低于对照值，而HMG-CoA还原酶mRNA水平正常。当对大鼠进行1、3或6周研究时，获得的结果无显著差异。这些结果总体表明，尽管胆固醇摄入量大幅增加，但7.5%壳聚糖配方可维持大鼠适当的胆固醇稳态。
