Apolipoprotein A-IMilano. Correlation between high density lipoprotein subclass distribution and triglyceridemia.

Abstract

Carriers of the apolipoprotein A-I unino (apo A-I M ) variant represent a selected group of subjects showing low levels of high density lipoprotein (HDL), variable hypertrlglycerldemia, and low prevalence of atherosclerotic vascular disease. The distribution of HDL subtractions and the correlation with abnormalities in triglycerlde transport were determined In these subjects. Sera from 24 apo A-I M carriers (A-I H + and from age-and sex-matched normollpldemlc controls (A-I u~) were analyzed by rate zonal ultracentrlrugatlon. The A-I H + subjects showed a marked decrease of HDL 3 mass with reduced flotation rates and major compositional alterations; the HDL 2 were nearly absent The HDL subclasses from 10 A-I u + subjects were resolved according to particle size by gradient gel eiectrophoresis (GGE). The HDL patterns detected In the carriers were unique In exhibiting a distinct peak In the (HDLuJgg, interval, undetectable In the controls. Three patterns reflecting the relative contributions of smaller (HDLjJgg. and larger (HDLj.)™ particles could be distinguished In the carriers, and these were clearly related to different triglycerlde and HDL cholesterol levels in plasma. These findings In a highly selected group of subjects with generally low HDL levels and quite variable triglyceridemia confirmed the existence of relationships between alterations In triglycerlde transport and abnormalities In the HDL subclass distribution, possibly reflecting the variable atherosclerotic risk in hypertrlglycerldemlc subjects. (Arteriosclerosis 7:426-435, July/August 1987)

Increased Cholesterol Efflux Potential of Sera From ApoA-I Milano Carriers and Transgenic Mice

“…The A-I M and A-I WT mice have low-normal serum ApoA-I levels, no lipid-free ApoA-I in serum, 18,31 and a similar HDL phospholipid/ApoA-I ratio. The distinct physicochemical properties of acceptor particles containing wild-type or mutant ApoA-I 18,28,34,35 may also contribute to the discrepancy between the present and previous findings, by affecting the interaction of HDL with scavenger receptor BI.…”

“…The REP, which provides an indirect estimation of the relative efficiency of acceptor particles to extract cholesterol from cells, 11 was higher in A-I M carriers than control subjects, suggesting a relative abundance of more efficient acceptors in the sera from A-I M carriers. Previous extensive studies on the characterization of HDL particles in these subjects demonstrate that A-I M HDL are smaller in size than control HDL, 28,34 a characteristic that has been associated with improved efficiency for cell cholesterol uptake. Moreover, efflux studies with reconstituted HDL show that particles containing a recombinant form of the disulfide-linked A-I M dimer are more efficient than A-I WT -containing particles in removing cholesterol from cultured cells, 36 possibly because of the unique conformation of the mutant ApoA-I on the surface of HDL.…”

“…17 HDL particles from A-I M carriers were enriched in triglycerides and phospholipids, and depleted in cholesteryl esters compared with control HDL (Table 2); the surface/core ratio was significantly higher in A-I M HDL than in control HDL (4.29Ϯ1.26 versus 3.25Ϯ0.49), indicative of a prevalence of small particles in the serum of A-I M carriers. 28 Cholesterol efflux data, expressed as percent efflux from Fu5AH cells during a 4-hour incubation, obtained with sera from A-I M carriers and controls, are shown in Figure 1. The average efflux value was 18% lower in A-I M carriers (25.0Ϯ4.2%) than in controls (30.4Ϯ3.3; PϽ0.001).…”

Targeted Replacement of Mouse Apolipoprotein A-I with Human ApoA-I or the Mutant ApoA-IMilano

“…In the A-I M k-in line, triglyceride elevation was, in fact, of minimal degree and did not attain statistical significance. Moreover, A-I M k-in mice displayed an HDL size distribution that lacks a subpopulation of very small particles present in both human carriers (55) and in the previously generated A-I M /A-II transgenic mice (33,34). A possible explanation for these differences may reside in the absence of human apoA-II in A-I M k-in mice.…”

Apolipoprotein A-IMilanoand 1-Palmitoyl-2-oleoyl Phosphatidylcholine Complex (ETC-216) Protects the in Vivo Rabbit Heart from Regional Ischemia-Reperfusion Injury

“…This variant protein was first discovered in the blood serum of a human subject living in the geographically isolated village of Limone sul Garda, Italy (Gualandri et al, 1985a). The human apoA-I Milano variants present with an extremely low level of HDL-C, mildly elevated triglycerides, and without premature cardiovascular disease (Franceschini et al, 1985(Franceschini et al, , 1987. Subsequently, additional carriers, all heterozygous for apoA-I Milano , with a similar dyslipidemia were identified (Gualandri et al, 1985b).…”