| First Author | Bowden KL | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 5 | Pages | 1191-1201 |
| PubMed ID | 29599133 | Mgi Jnum | J:285128 |
| Mgi Id | MGI:6385435 | Doi | 10.1161/ATVBAHA.117.310507 |
| Citation | Bowden KL, et al. (2018) LAL (Lysosomal Acid Lipase) Promotes Reverse Cholesterol Transport In Vitro and In Vivo. Arterioscler Thromb Vasc Biol 38(5):1191-1201 |
| abstractText | 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 [(3)H]-cholesteryl oleate-labeled acetylated low-density lipoprotein showed impaired efflux of released [(3)H]-cholesterol to apoA-I (apolipoprotein A-I), with normalization of [(3)H]-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 [(3)H]-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 (3)H-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. |
