Effect of gemfibrozil treatment in hypercholesterolemia on low density lipoprotein (LDL) subclass distribution and LDL-cell interaction.
Gemfibrozil, a widely used fibric acid derivative, corrects hypercholesterolemia in a non-negligible fraction of patients. To investigate the mechanism of the cholesterol-lowering activity of fibric acids, a study was performed in 12 type IIa hyperlipidemic patients treated with gemfibrozil for 12 weeks. Changes in low density lipoprotein (LDL) structure and composition, agonist capacity of LDL against the LDL-receptor in human skin fibroblasts, LDL-receptor activity in mononuclear cells, lecithin:cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activity, were evaluated. Plasma total and LDL cholesterol levels decreased by 17% and 20% after 12 weeks of treatment, the reduction being directly correlated with the baseline levels (r = 0.75 and 0.78, respectively). The mean LDL diameter increased significantly, from 25.5 to 26.1 nm, while the relative content of small LDL particles (< 25.1 nm) increased from 23.4% to 32.8% of total LDL. Neither the apolipoprotein (apo) B secondary structure nor the affinity of LDL for the LDL-receptor of fibroblasts were affected. The LDL-receptor activity in patients' mononuclear cells increased 3-fold, the rise being unrelated to the plasma cholesterol reduction. LCAT activity did not change, while CETP activity was reduced by 25% (P = 0.13) after treatment. These findings indicate that gemfibrozil causes significant changes in LDL structure that do not, however, affect the LDL interaction with peripheral cells.
Franceschini
G
G
Center E. Grossi Paoletti, Institute of Pharmacological Sciences, University of Milano, Italy.
Lovati
M R
MR
Manzoni
C
C
Michelagnoli
S
S
Pazzucconi
F
F
Gianfranceschi
G
G
Vecchio
G
G
Sirtori
C R
CR
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001053:Apolipoproteins / Q000097:blood; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015248:Gemfibrozil / Q000008:administration & dosage / Q000627:therapeutic use*; D006023:Glycoproteins; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006023:Glycoproteins; D008074:Lipoproteins; D010713:Phosphatidylcholines; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D015248:Gemfibrozil