APOLIPOPROTEIN-A-I(MILANO) - SEX-RELATED DIFFERENCES IN THE CONCENTRATION AND COMPOSITION OF APOA-I-CONTAINING AND APO-B-CONTAINING LIPOPROTEIN PARTICLES

The presence of apolipoprotein (apo) A-I(Milano) (A-I(M)) mutant of apoA- I has a marked effect on plasma lipoproteins of A-I(M) carriers including variable hypertriglyceridemia, increased levels of very low density lipoproteins (VLDL), slightly elevated levels of triglyceride-enriched low density lipoproteins (LDL) and greatly reduced levels of high density lipoproteins (HDL). To gain further insight into this dyslipoproteinemic syndrome characterized clinically by the absence of coronary artery disease, we have determined the concentration and composition of apoA- and apoB- containing lipoprotein families in four male and four female carriers and corresponding normal controls. Results have shown that A-I(M) carriers have significantly reduced levels of lipoprotein (LP) A-I (45%), LP-A-I:A-II (60%), and LP-A-II (70%) and significantly increased levels of cholesterol- rich LP-B (67%) and triglyceride-rich LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E (65%) particles compared to controls. However, there were significant sex- related differences in the levels of apoA- and apoB-containing lipoproteins. Female carriers had significantly higher concentrations of LP-A-I (39 ± 10 vs. 12 ± 6 mg/dl) and LP-A-I:A-II (48 ± 11 vs. 30 ± 6 mg/dl) than male carriers. Furthermore, female carriers had higher levels of LP-B:C (23 ± 18 vs. 6 ± 5 mg/dl) and LP-A-II:B:C:D:E (13 ± 6 vs. 2.3 ± 0.8 mg/dl) but lower concentrations of LP-B (103 ± 52 vs. 152 ± 54 mg/dl) and LP-B:C:E (5 ± 2.5 vs. 13 ± 8 mg/dl) than male carriers. In general, the levels of LP- A-I and LP-A-I:A-II particles correlated positively with the levels of all three types of triglyceride-rich lipoproteins (LP-B(c)) and negatively with the levels of LP-B particles. A comparative study of lipoprotein families in several dyslipoproteinemic states characterized by low levels of HDL has indicated that the characteristic lipoprotein particle profile of A-I(M) carriers results most probably from the selective effect of apoA-I(M) mutant rather than a general reduction in HDL levels. It appears that increased levels of LP-A-II:B:C:D:E particles, an inefficient substrate for lipoprotein lipase, and structurally defective LP-A-I:A-II particles, the normal acceptors of minor apolipoproteins released during lipolysis of triglyceride- rich lipoproteins, may be the main contributing factors to moderate hypertriglyceridemia characteristic of A-I(M) carriers.