Improvement in the regulation of cellular cholesterologenesis in diabetes: the effect of reduction in serum cholesterol by simvastatin.
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 l-1 to 5.5 +/- 0.2 mmol l-1 (p less than 0.001) and LDL-cholesterol by 35 +/- 4% from 5.7 +/- 0.2 to 3.6 +/- 0.1 mmol l-1 (p less than 0.001). The esterified/free cholesterol ratio in LDL also decreased from 2.75 +/- 0.18 to 1.94 +/- 0.10 (p less than 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 mumol g-protein-1 (p less than 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 less than 0.001) following simvastatin. The activity of acyl coenzyme A:cholesterol-0-acyltransferase (ACAT) increased significantly by 55 +/- 18% (p less than 0.05) after treatment. Cholesterol synthesis in patients' mononuclear cells correlated positively (r = 0.66, p less than 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 less than 0.05) with the esterified/free cholesterol ratio of the LDL following treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Owens
D
D
Department of Biochemistry, Royal College of Surgeons in Ireland, Dublin.
Stinson
J
J
Collins
P
P
Johnson
A
A
Tomkin
G H
GH
D000085:Acetates / Q000378:metabolism; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008875:Middle Aged; D019821:Simvastatin; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D000085:Acetates; D000924:Anticholesteremic Agents; D002784:Cholesterol; D006442:Glycated Hemoglobin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; D002785:Sterol O-Acyltransferase