Boucher P, de Lorgeril M, Salen P, Crozier P, Delaye J, Vallon J J, Geyssant A, Dante R
The Laboratoire de Biochimie et Pharmaco-Toxicologie, CNRS UMR-5641, Université Claude Bernard, Lyon, France.
Lipids. 1998 Dec;33(12):1177-86. doi: 10.1007/s11745-998-0321-8.
We investigated the possibility that dietary cholesterol downregulates the expression of low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase genes of circulating mononuclear cells in vivo in healthy humans. We also studied the variations of the LDL receptor-related protein (LRP) gene in the same conditions. Dieters (n = 5) were submitted to a 4-d fat restriction (mean cholesterol intake: 6+/-4 mg/d), followed by a 7-d cholesterol (a mean of 791+/-150 mg/d) supplementation. Controls (n = 3) did not change their diet. During fat restriction, serum total and LDL cholesterol decreased significantly (P < 0.05), and LDL receptor and HMG-CoA reductase mRNA copy numbers in mononuclear cells increased by 57 and 147%, respectively (P < 0.05). After reintroducing cholesterol, serum cholesterol was stable whereas LDL receptor and HMG-CoA reductase mRNA decreased by 46 and 72% (P < 0.05) and LRP mRNA increased by 59% (P < 0.005). The changes in LDL receptor and HMG-CoA reductase mRNA abundance were correlated (r = +0.79, P = 0.02) during cholesterol reintroduction as were LDL receptor and LRP mRNA levels, but negatively (r = -0.70, P = 0.05). Also, 70% of the variability in LRP mRNA (P < 0.005) was explained by dietary cholesterol. Thus, the basic mechanisms regulating cellular cholesterol content, the coordinate feedback repression of genes governing the synthesis and uptake of cholesterol, are operating in vivo in humans. However, serum cholesterol did not increase in response to dietary cholesterol, suggesting that these mechanisms may not play as predominant a role as previously believed in the short-term control of serum cholesterol in vivo in humans. A new finding is that LRP gene is also sensitive to dietary cholesterol, suggesting that it may participate in the control of serum cholesterol. Further in vivo studies in humans are warranted to explore the molecular mechanisms of the physiological response to dietary cholesterol in humans.
我们研究了在健康人体内，膳食胆固醇是否会下调循环单核细胞中低密度脂蛋白（LDL）受体和3-羟基-3-甲基戊二酰辅酶A（HMG）-CoA还原酶基因的表达。我们还研究了在相同条件下低密度脂蛋白受体相关蛋白（LRP）基因的变化。节食者（n = 5）先进行为期4天的脂肪限制饮食（平均胆固醇摄入量：6±4毫克/天），随后进行为期7天的胆固醇补充（平均791±150毫克/天）。对照组（n = 3）饮食不变。在脂肪限制期间，血清总胆固醇和低密度脂蛋白胆固醇显著下降（P < 0.05），单核细胞中LDL受体和HMG-CoA还原酶mRNA拷贝数分别增加了57%和147%（P < 0.05）。重新引入胆固醇后，血清胆固醇保持稳定，而LDL受体和HMG-CoA还原酶mRNA分别下降了46%和72%（P < 0.05），LRP mRNA增加了59%（P < 0.005）。在重新引入胆固醇期间，LDL受体和HMG-CoA还原酶mRNA丰度的变化呈正相关（r = +0.79，P = 0.02），LDL受体和LRP mRNA水平也是如此，但呈负相关（r = -0.70，P = 0.05）。此外，70%的LRP mRNA变异性（P < 0.005）可由膳食胆固醇解释。因此，调节细胞胆固醇含量的基本机制，即对控制胆固醇合成和摄取的基因进行协同反馈抑制，在人体内是起作用的。然而，血清胆固醇并未因膳食胆固醇而升高，这表明这些机制在人体内血清胆固醇的短期体内控制中可能不像以前认为的那样起主要作用。一个新发现是LRP基因也对膳食胆固醇敏感，这表明它可能参与血清胆固醇的控制。有必要在人体中进行进一步的体内研究，以探索人体对膳食胆固醇生理反应的分子机制。
