Abstract
Alagille syndrome is associated with bile duct paucity resulting in liver disease. Patients can be divided into mildly and severely icteric groups, with both groups having altered lipoproteins. The incidence of ischemic heart disease is rare in severely cholestatic children despite increased total cholesterol and decreased high density lipoprotein cholesterol (HDL-C). The present studies examine the impact of altered lipid and lipoproteins on scavenger receptor class B type I (SR-BI)- and ABCA1-mediated efflux to serum from both groups. Efflux was compared with serum from 29 patients (15 with normal plasma cholesteryl ester, 14 with low cholesteryl ester). Efflux via SR-BI and ABCA1 was studied using cell systems having either low or high expression levels of these receptors. SR-BI efflux was lower (P = 0.04) with serum from severely icteric patients (3.9 +/- 1.4%) compared with serum from mildly icteric patients (5.1 +/- 1.4%) and was positively correlated with HDL-C and its apolipoproteins. SR-BI-mediated efflux was not correlated with any particular mature HDL but was negatively correlated with small lipid-poor prebeta-1 HDL. Consistent with severely icteric patients having high prebeta-1 HDL levels, the ABCA1 efflux was significantly higher with their serum (4.8 +/- 2.2%) compared with serum from mildly icteric patients (2.0 +/- 0.6%) and was positively correlated with prebeta-1 HDL. These studies demonstrated that prebeta-1 HDL is the preferred acceptor for ABCA1 efflux, whereas many particles mediate SR-BI efflux.
Highlights
Alagille syndrome is associated with bile duct paucity resulting in liver disease
Serum lipid and apolipoprotein composition Because studies have shown that serum cholesteryl ester (CE) levels are indicative of serum lipoprotein X (LpX) levels and LCAT activity in subjects with Alagille syndrome [2], the patients were assigned to one of two groups according to their serum CE levels [Ն65% of total cholesterol (TC) or Ͻ65% of TC]
Consistent with percentage serum CE being a marker for LCAT activity, high density lipoprotein cholesterol (HDL-C) levels in group 2 patients were 38% lower compared with HDL-C levels in group 1 patients (Table 1)
Summary
Tissue culture plasticware was obtained through Falcon (Lincoln, NJ). Calf serum (CS), FBS, BSA, penicillin, and streptomycin were purchased from Sigma Chemical Co. SR-BI-mediated cholesterol efflux was measured using control and SR-BI-transfected COS-7 cells as previously described [25]. After 24 h, the cells were labeled by incubation for 24 h in 1% FBS RPMI containing 12 Ci of [3H]cholesterol and 2 g of CP113,818 per milliliter. Medium containing the human serum to be tested diluted to 1% was added to the cells and incubated at 37ЊC. This calculation controls for the contribution of other efflux mechanisms and yields data that are more specific for the contribution of ABCA1 or SR-BI It should be noted, that in both cases the control cells lack significant levels of either ABCA1 (no cpt-cAMP treatment) or SR-BI (transfected with empty vector) [17, 18, 26]. All statistical tests were two-tailed, and a value of P Ͻ 0.05 was considered statistically significant
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