Improvement in the Regulation of Cellular Cholesterologenesis in Diabetes: the Effect of Reduction in Serum Cholesterol by Simvastatin

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Abstract
Cellular cholesterol homeostasis was examined in 11 hypercholesterolaemic Type 2 diabetic patients prior to and following reduction of serum cholesterol using simvastatin, an inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMGCoA) reductase. Following 12 weeks of treatment with simvastatin (10–40 mg day−1), serum cholesterol decreased by 30 ± 3% from 7.8 ± 0.2 mmol I−1 to 5.5 ± 0.2 mmol I−1 (p < 0.001) and LDL‐cholesterol by 35 ± 4% from 5.7 ± 0.2 to 3.6 ± 0.1 mmol I−1 (p < 0.001). The esterified/free cholesterol ratio in LDL also decreased from 2.75 ± 0.18 to 1.94 ± 0.10 (p < 0.01) after treatment. Cellular cholesterol synthesis, measured by [14C] acetate incorporation into mononuclear leucocytes, decreased by 39 ± 11% from 231 ± 13 to 140 ± 25 μmol g‐protein−1 (p < 0.01). The degree of suppression of [14C]acetate incorporation into cholesterol in normal mononuclear cells by diabetic patients' LDL increased from 32.1 ± 4.0% to 48.8 ± 2.5% (p < 0.001) following simvastatin. The activity of acyl coenzyme A:cholesterol‐0‐acyltransferase (ACAT) increased significantly by 55 ± 18% (p < 0.05) after treatment. Cholesterol synthesis in patients' mononuclear cells correlated positively (r = 0.66, p < 0.05) with the esterified/free cholesterol ratio of their LDL, while suppression of cholesterol synthesis by patients' LDL correlated negatively (r = −0.64, p < 0.05) with the esterified/free cholesterol ratio of the LDL following treatment. Thus, abnormally esterified LDL particles found in hypercholesterolaemic diabetic patients can be modified by the hypocholesterolaemic agent simvastatin and this compositional alteration in LDL is associated with increased cellular cholesterol esterification.

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