The effects of hypercholesterolaemia, simvastatin and dietary fat on the low density lipoprotein receptor of unstimulated mononuclear cells.

The in vivo expression and regulation of the LDL receptor of circulating mononuclear cells was studied using a sensitive spectrophotometric assay with low density lipoproteins conjugated to colloidal gold (LDL-gold). The high plasma cholesterol of familial hypercholesterolemic subjects was shown to be related to a low in vivo LDL receptor activity; cells from a homozygote had virtually no activity and those from 24 heterozygotes expressed 45% of the activity of cells from 35 normals. The average receptor activity of cells from 18 polygenic hypercholesterolemic (PH) subjects was not significantly different from normal but a low expression may have been a factor in six of these subjects. Simvastatin increased the LDL receptor activity of cells from the PH subjects by 70% while lowering their plasma cholesterol by 26%, but reducing the fat intake from 38% to 20% of energy and cholesterol from 239 to 96 mg/day had no effect on the receptor despite a 10% reduction in plasma cholesterol. Upregulation of the LDL receptor may therefore have been involved in the lowering of plasma cholesterol by simvastatin but not by the reduction in dietary fat and cholesterol.

Is fat restriction needed with HMGCoA reductase inhibitor treatment?

Fourteen women and five men participated in a 20-week controlled, cross-over trial of the interaction of simvastatin, an HMGCoA reductase inhibitor, with high and low fat diets. Simvastatin was found to be just as effective at lowering LDL cholesterol whether the subjects were on a 22% fat diet or a 38% fat diet (25% and 29% falls, respectively). Nevertheless, the lowest cholesterol levels were achieved by combining simvastatin with a low fat diet, the latter adding a further 5% reduction in plasma cholesterol. Simvastatin plus a low or high fat diet increased HDL cholesterol by 10.0% and 2.9% respectively (P = 0.003 overall) and reduced triglyceride concentration by 15.9% and 19% respectively (P less than 0.001). Significant diet-drug interactions were seen in LDL and HDL3 cholesterol. Simvastatin blunted the effect of dietary fat change so that the difference in LDL cholesterol, which was 0.71 mmol/l between high and low fat in the absence of simvastatin, was only 0.22 mmol/l with simvastatin. On a high fat diet, simvastatin produced almost no rise in HDL3 cholesterol whereas on a low fat diet HDL3 cholesterol was increased by 8.8% with simvastatin. The cholesterol content of VLDL and LDL were significantly reduced by simvastatin. The effects of diet and drug on apoproteins A-I and B resembles those on HDL and LDL cholesterol. The findings show interactions between simvastatin and dietary fat which have a bearing on the treatment of hypercholesterolemia.