The effect of reduction of lipoprotein (a) on cellular cholesterol synthesis in non-diabetic and type 2 diabetic subjects.
This study investigates the effect of Lipoprotein (a) (Lp(a)) on cellular cholesterol synthesis in non-diabetic (n = 7) and Type 2 (non-insulin-dependent) diabetic subjects (n = 7) with elevated levels of Lp(a) (> 20 mg/dl). N-Acetylcysteine was used to lower Lp(a) in the control subjects and their lipoproteins were re-examined after 7 days of treatment. Low-density lipoprotein (LDL) was isolated and separated from Lp(a) by sequential ultracentrifugation. Regulation of cellular cholesterol synthesis was assessed by measuring incorporation of [14C]acetate into mononuclear leucocytes in the presence of LDL and Lp(a). Cellular cholesterol content was determined by a fluorometric assay. Delivery of cholesterol to the cell was examined using [3H]cholesteryl oleate-labelled LDL or Lp(a). LDL (5 micrograms/ml) from non-diabetic subjects suppressed cellular cholesterol synthesis by 66.2%, while Lp(a) at a similar concentration only suppressed cholesterol synthesis by 5.8% (P < 0.001). At a concentration of 20 micrograms/ml, Lp(a) suppressed cholesterol synthesis by 31.7%. The situation was similar in the diabetic subjects. Serum LDL cholesterol in non-diabetic subjects was 4.2 +/- 0.5 mmol/l and the LDL esterified/free cholesterol ratio was 2.6 +/- 0.2. Following treatment with N-acetylcysteine, LDL cholesterol did not change, while Lp(a) decreased significantly by 24% (P < 0.05). The LDL esterified/free cholesterol ratio decreased to 2.2 +/- 0.2 (P < 0.05) and there was a significant increase in the ability of the subjects LDL to inhibit cellular cholesterol synthesis (P < 0.05). There was a significant negative correlation between plasma Lp(a) and the ability of the patients' LDL to inhibit cellular cholesterol synthesis (r = -0.68, P < 0.01). [3H]Cholesteryl-oleate-LDL (5 micrograms/ml) delivered 266 +/- 13 ng cholesteryl oleate/mg cell protein, while it took 20 micrograms of [3H]cholesteryl oleate-labelled-Lp(a) to deliver a similar concentration (315 +/- 21 ng cholesteryl oleate/mg cell protein). In conclusion it appears possible that the atherogenicity of Lp(a) may be associated with its effect on the LDL receptor which alters LDL receptor uptake, LDL composition and cellular cholesterol synthesis.
Gilligan
S
S
Department of Biochemistry, Royal College of Surgeons in Ireland, Dublin.
Owens
D
D
Stinson
J
J
Collins
P
P
Johnson
A
A
Tomkin
G H
GH
D000111:Acetylcysteine / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis*; D002788:Cholesterol Esters / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D017270:Lipoprotein(a) / Q000097:blood* / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000097:blood / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction
D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; C014409:cholesteryl oleate; D002784:Cholesterol; D000111:Acetylcysteine