LAL (lysosomal acid lipase) promotes reverse cholesterol transport in vitro and in vivo

Kristin L. Bowden, Joshua A. Dubland, Teddy Chan, You Hai Xu, Gregory A. Grabowski, Hong Du, Gordon A. Francis

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1191-1201
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume38
Issue number5
DOIs
StatePublished - Jan 1 2018

Keywords

  • Animals
  • Cholesterol
  • Macrophages
  • Mice
  • Sterol esterase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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