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Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells.

ABSTRACT: We previously reported that HIV protease inhibitor, ritonavir, could inhibit cholesterol efflux and induce endothelial dysfunction. In this study, we further determined the effects and molecular mechanisms of a clinically relevant combination of highly active antiretroviral therapy (HAART) drugs on in vitro cholesterol efflux from human macrophage-derived foam cells. Foam cells derived from human monocyte cell line (THP-1) and periphery blood mononuclear cells (PBMCs) treated with HAART drugs including stavudine, didanosine and indinavir individually or in combination of three drugs (3-plex), followed by the initiation of cholesterol efflux with apolipoprotein A-I (apoA-I). Clinically relevant concentrations of HAART 3-plex significantly reduced cholesterol efflux in foam cells derived from THP-1 and PBMCs. HAART 3-plex significantly reduced the intracellular cholesterol transport molecule caveolin-1, whereas it increased superoxide anion production in THP-1 foam cells as compared with controls. Furthermore, mitochondrial membrane potential was significantly reduced, whereas the expression of NADPH oxidase subunit p67(phox) was increased in HAART 3-plex-treated macrophages. Consequently, antioxidants including ginsenosides Rb1 and Rg1, S-allyl cysteine sulphoxide (SACS), simvastatin (SVT) and vitamin E significantly abolished HAART 3-plex-induced inhibition of cholesterol efflux. Therefore, HAART drugs significantly inhibit cholesterol efflux from human macrophage-derived foam cells through downregulation of caveolin-1 and increase of oxidative stress.

SUBMITTER: Wang X

PROVIDER: S-EPMC2787635 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells.

Wang Xinwen X Liao Dan D Lin Peter H PH Yao Qizhi Q Chen Changyi C

Laboratory investigation; a journal of technical methods and pathology 20090921 12

We previously reported that HIV protease inhibitor, ritonavir, could inhibit cholesterol efflux and induce endothelial dysfunction. In this study, we further determined the effects and molecular mechanisms of a clinically relevant combination of highly active antiretroviral therapy (HAART) drugs on in vitro cholesterol efflux from human macrophage-derived foam cells. Foam cells derived from human monocyte cell line (THP-1) and periphery blood mononuclear cells (PBMCs) treated with HAART drugs in ...[more]

PMID: 19770838

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Project description:Macrophage autophagy is a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid droplets (LDs) to maintain cellular lipid homeostasis. Selective autophagy relies on tags such as ubiquitin and a set of selectivity factors including selective autophagy receptors (SARs) to label specific cargo for degradation. Originally described in yeast cells, "lipophagy" refers to the degradation of LDs by autophagy. Yet, how LDs are targeted for autophagy is poorly defined. Here, we employed mass spectrometry to identify lipophagy factors within the macrophage foam cell LD proteome. In addition to structural proteins (e.g., PLIN2), metabolic enzymes (e.g., ACSL) and neutral lipases (e.g., PNPLA2), we found the association of proteins related to the ubiquitination machinery (e.g., AUP1) and autophagy (e.g., HMGB, YWHA/14-3-3 proteins). The functional role of candidate lipophagy factors (a total of 91) was tested using a custom siRNA array combined with high-content cholesterol efflux assays. We observed that knocking down several of these genes, including Hmgb1, Hmgb2, Hspa5, and Scarb2, significantly reduced cholesterol efflux, and SARs SQSTM1/p62, NBR1 and OPTN localized to LDs, suggesting a role for these in lipophagy. Using yeast lipophagy assays, we established a genetic requirement for several candidate lipophagy factors in lipophagy, including HSPA5, UBE2G2 and AUP1. Our study is the first to systematically identify several LD-associated proteins of the lipophagy machinery, a finding with important biological and therapeutic implications. Targeting these to selectively enhance lipophagy to promote cholesterol efflux in foam cells may represent a novel strategy to treat atherosclerosis.Abbreviations: ADGRL3: adhesion G protein-coupled receptor L3; agLDL: aggregated low density lipoprotein; AMPK: AMP-activated protein kinase; APOA1: apolipoprotein A1; ATG: autophagy related; AUP1: AUP1 lipid droplet regulating VLDL assembly factor; BMDM: bone-marrow derived macrophages; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; BSA: bovine serum albumin; CALCOCO2: calcium binding and coiled-coil domain 2; CIRBP: cold inducible RNA binding protein; COLGALT1: collagen beta(1-O)galactosyltransferase 1; CORO1A: coronin 1A; DMA: deletion mutant array; Faa4: long chain fatty acyl-CoA synthetase; FBS: fetal bovine serum; FUS: fused in sarcoma; HMGB1: high mobility group box 1; HMGB2: high mobility group box 2: HSP90AA1: heat shock protein 90: alpha (cytosolic): class A member 1; HSPA5: heat shock protein family A (Hsp70) member 5; HSPA8: heat shock protein 8; HSPB1: heat shock protein 1; HSPH1: heat shock 105kDa/110kDa protein 1; LDAH: lipid droplet associated hydrolase; LIPA: lysosomal acid lipase A; LIR: LC3-interacting region; MACROH2A1: macroH2A.1 histone; MAP1LC3: microtubule-associated protein 1 light chain 3; MCOLN1: mucolipin 1; NBR1: NBR1, autophagy cargo receptor; NPC2: NPC intracellular cholesterol transporter 2; OPTN: optineurin; P/S: penicillin-streptomycin; PLIN2: perilipin 2; PLIN3: perilipin 3; PNPLA2: patatin like phospholipase domain containing 2; RAB: RAB, member RAS oncogene family; RBBP7, retinoblastoma binding protein 7, chromatin remodeling factor; SAR: selective autophagy receptor; SCARB2: scavenger receptor class B, member 2; SGA: synthetic genetic array; SQSTM1: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; TFEB: transcription factor EB; TOLLIP: toll interacting protein; UBE2G2: ubiquitin conjugating enzyme E2 G2; UVRAG: UV radiation resistance associated gene; VDAC2: voltage dependent anion channel 2; VIM: vimentin.

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Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells.

Publications

Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells.

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