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Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.

ABSTRACT: Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) markedly attenuated the cholesterol ester accumulation in oxidized low density lipoprotein-loaded macrophages. Notably, AICAR treatment significantly increased ATP-binding cassette transporters G1 (Abcg1) mRNA and protein levels without affecting mRNA and protein expression of ABCA1, scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI (SR-BI), and cholesterol synthesis-related genes. The up-regulation of Abcg1 by AICAR was independent of the liver X receptor/retinoid X receptor pathway but dependent on ERK activation. AICAR elevates Abcg1 expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the Abcg1 mRNA 3'-UTR responsible for the regulatory effect of AICAR. Prevention of ABCG1 expression by small interfering RNA abolished the AICAR-mediated attenuation on foam cell formation. Furthermore, increased ABCG1 expression and reduced lipid accumulation were demonstrated in AICAR-treated macrophages isolated from apolipoprotein E-deficient mice (apoE(-/-) mice). AICAR treatment also inhibited atherosclerotic plaque formation in apoE(-/-) mice. Our findings elucidate a precise mechanism involved in the prevention of atherogenesis by AMPK.

SUBMITTER: Li D

PROVIDER: S-EPMC2963409 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.

Li Dan D Wang Duan D Wang Yun Y Ling Wenhua W Feng Xiang X Xia Min M

The Journal of biological chemistry 20100816 43

Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carbox ...[more]

PMID: 20713354

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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.

Dataset Information

Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.

Publications

Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.

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