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

Arterioscler Thromb Vasc Biol. 2018 May;38(5):1191-1201. doi: 10.1161/ATVBAHA.117.310507. Epub 2018 Mar 29.

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 [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.

Keywords: animals; cholesterol; macrophages; mice; sterol esterase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / metabolism
  • Animals
  • Apolipoprotein A-I / metabolism
  • Biological Transport
  • Cell Line
  • Cholesterol / blood
  • Cholesterol / metabolism*
  • Feces / chemistry
  • Lipoproteins / genetics
  • Lipoproteins / metabolism
  • Liver / metabolism
  • Macrophages, Peritoneal / enzymology*
  • Mice, 129 Strain
  • Mice, Knockout
  • Sterol Esterase / deficiency
  • Sterol Esterase / genetics
  • Sterol Esterase / metabolism*

Substances

  • ABCA1 protein, mouse
  • ABCG1 protein, mouse
  • ABCG5 protein, mouse
  • ABCG8 protein, mouse
  • APOA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • Apolipoprotein A-I
  • Lipoproteins
  • Cholesterol
  • LIPA protein, human
  • Sterol Esterase
  • lysosomal acid lipase, mouse