We compared the consequences of an ABCA1 mutation that produced an apparent lack of
atherosclerosis (Tangier family 1, N935S) with an ABCA1 mutation with functional ABCA1 knockout that was associated with severe
atherosclerosis (Tangier family 2, Leu(548):Leu(575)-End), using primary and
telomerase-immortalized fibroblasts.
Telomerase-immortalized Tangier fibroblasts of family 1 (TT1) showed 30% residual
cholesterol efflux capacity in response to
apolipoprotein A-I, whereas
telomerase-immortalized Tangier fibroblasts of family 2 (TT2) showed only 20%. However, there were a number of secondary differences that were often stronger and may help to explain the more rapid development of
atherosclerosis in family 2. First, the total cellular
cholesterol content increase was 2-3-fold and 3-5-fold in TT1 and TT2 cells, respectively. The corresponding increase in esterified
cholesterol concentration was 10- and 40-fold, respectively. Second, 24-, 25-, and
27-hydroxycholesterol concentrations were moderately increased in TT1 cells, but were increased as much as 200-fold in TT2 cells. Third,
cholesterol biosynthesis was moderately decreased in TT1 cells, but was markedly decreased in TT2 cells. Fourth, potentially atheroprotective LXR-dependent SREBP1c signaling was normal in TT1, but was rather suppressed in TT2 cells. Cultivated primary Tangier fibroblasts were characterized by
premature aging in culture and were associated with less obvious biochemical differences. In summary, these results may help to understand the differential atherosclerotic susceptibility in
Tangier disease and further demonstrate the usefulness of
telomerase-immortalized cells in studying this cellular phenotype. The data support the contention that side chain-oxidized
oxysterols are strong suppressors of
cholesterol biosynthesis under specific pathological conditions in humans.