Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses.
OBJECTIVE
Adiponectin is an adipokine that exerts anti-inflammatory and anti-atherogenic effects during macrophage transformation into foam cells. To further understand the signaling pathways of adiponectin involved in macrophage foam cell transformation, we investigated the roles of two adiponectin receptors (AdipoR1 and AdipoR2) and their downstream adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in mediating adiponectin action on foam cell transformation.


RESULTS
Transfections were performed to overexpress or knockdown AdipoR1 or AdipoR2 genes in human THP-1 monocytes. Lentiviral-shRNAs were also used to knockdown APPL1 gene in these cells. Foam cell transformation was induced via exposure to oxidized low-density lipoprotein (oxLDL). Our results showed that both AdipoR1 and AdipoR2 were critical for transducing the adiponectin signal that suppresses lipid accumulation and inhibits transformation from macrophage to foam cell. However, AdipoR1 and AdipoR2 were found to have differential effects in diminishing proinflammatory responses. While AdipoR1 was required by adiponectin to suppress tumor necrosis factor alpha (TNFα) and monocyte chemotactic protein 1 (MCP-1) gene expression, AdipoR2 served as the dominant receptor for adiponectin suppression of scavenger receptor A type 1 (SR-AI) and upregulation of interleukin-1 receptor antagonist (IL-1Ra). Knockdown of APPL1 significantly abrogated the ability of adiponectin to inhibit lipid accumulation, SR-AI and nuclear factor-κB (NF-κB) gene expression, and Akt phosphorylation in macrophage foam cells.


CONCLUSIONS
In current studies, we have demonstrated that adiponectin's abilty to suppress macrophage lipid accumulation and foam cell formation is mediated through AdipoR1 and AdipoR2 and the APPL1 docking protein. However, AdipoR1 and AdipoR2 exhibited a differential ability to regulate inflammatory cytokines and SR-A1. These novel data support the idea that the adiponectin-AdipoR1/2-APPL1 axis may serve as a potential therapeutic target for preventing macrophage foam cell formation and atherosclerosis.
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-3360, United States.
Ling
L
Tian
Nanlan
N
Luo
Xiaolin
X
Zhu
Byung-Hong
BH
Chung
W Timothy
WT
Garvey
Yuchang
Y
Fu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
C499918:ADIPOQ protein, human; C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; C099252:oxidized low density lipoprotein; C548898:steroid receptor RNA activator, human; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt