Effect of dietary cholesterol on low density lipoprotein-receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor-related protein mRNA expression in healthy humans

We investigated the possibility that dietary cholesterol downregulates the expression of low density lipoprotein (LDL) receptor and 3-hydroxy-3-methyl glutaryl (HMG)-CoA reductase genes of circulating mononuclear cells in vivo in healthy humans. We also studied the variations of the LDL receptor-rela ted protein (LRP) gene in the same conditions. Dieters (n = 5) were submitt ed to a 4-d fat restriction (mean cholesterol intake: 6 +/- 4 mg/d), follow ed by a 7-d cholesterol (a mean of 791 +/- 150 mg/d) supplementation. Contr ols (n = 3) did not change their diet. During fat restriction, serum total and LDL cholesterol decreased significantly (P < 0.05), and LDL receptor an d HMG-CoA reductase mRNA copy numbers in mononuclear cells increased by 57 and 147%, respectively (P < 0.05). After reintroducing cholesterol, serum c holesterol was stable whereas LDL receptor and HMG-CoA reductase mRNA decre ased by 46 and 72% (P < 0.05) and LRP mRNA increased by 59% (P < 0.005). Th e changes in LDL receptor and HMG-CoA reductase mRNA abundance were correla ted (r = +0.79, P = 0.02) during cholesterol reintroduction as were LDL rec eptor 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 cholest erol. Thus, the basic mechanisms regulating cellular cholesterol content, t he coordinate feedback repression of genes governing the synthesis and upta ke of cholesterol, are operating in vivo in humans. However, serum choleste rol did not increase in response to dietary cholesterol, suggesting that th ese 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 findi ng is that LRP gene is also sensitive to dietary cholesterol, suggesting th at 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.