LAL (Lysosomal Acid Lipase) Promotes Reverse Cholesterol Transport In Vitro and In Vivo.

OBJECTIVE:To explore the role of LAL (lysosomal acid lipase) in macrophage cholesterol efflux and whole-body reverse cholesterol transport. APPROACH AND RESULTS:Immortalized peritoneal macrophages from lal^-/- mice showed reduced expression of ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1), reduced production of the regulatory oxysterol 27-hydroxycholesterol, and impaired suppression of cholesterol synthesis on exposure to acetylated low-density lipoprotein when compared with lal^+/+ macrophages. LAL-deficient mice also showed reduced hepatic ABCG5 (ATP-binding cassette transporter G5) and ABCG8 (ATP-binding cassette transporter G8) expression compared with lal^+/+ mice. LAL-deficient macrophages loaded with [³H]-cholesteryl oleate-labeled acetylated low-density lipoprotein showed impaired efflux of released [³H]-cholesterol to apoA-I (apolipoprotein A-I), with normalization of [³H]-cholesteryl ester levels and partial correction of ABCA1 expression and cholesterol efflux to apoA-I when treated with exogenous rhLAL (recombinant human LAL protein). LAL-deficient mice injected intraperitoneally with lal^-/- macrophages cholesterol loaded and labeled in the same way exhibited only 1.55±0.35% total injected [³H]-cholesterol counts appearing in the feces for 48 h (n=30), compared with 5.38±0.92% in lal^+/+ mice injected with labeled lal^+/+ macrophages (n=27), P<0.001. To mimic the therapeutic condition of delivery of supplemental LAL in vivo, injection of labeled lal^-/- macrophages into lal^+/+ mice resulted in a significant increase in reverse cholesterol transport (2.60±0.46% of ³H-cholesterol counts in feces at 48 hours [n=19]; P<0.001 when compared with injection into lal^-/- mice). CONCLUSIONS:These results indicate a critical role for LAL in promoting both macrophage and whole-body reverse cholesterol transport and the ability of supplemental LAL to be taken up and correct reverse cholesterol transport in vivo.

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