PMID- 22227293 OWN - NLM STAT- MEDLINE DCOM- 20120612 LR - 20211021 IS - 1879-1484 (Electronic) IS - 0021-9150 (Print) IS - 0021-9150 (Linking) VI - 221 IP - 1 DP - 2012 Mar TI - Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses. PG - 66-75 LID - 10.1016/j.atherosclerosis.2011.12.014 [doi] AB - 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. METHODS AND 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 (TNFalpha) 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-kappaB (NF-kappaB) 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. CI - Copyright A(c) 2011 Elsevier Ireland Ltd. All rights reserved. FAU - Tian, Ling AU - Tian L AD - Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-3360, United States. FAU - Luo, Nanlan AU - Luo N FAU - Zhu, Xiaolin AU - Zhu X FAU - Chung, Byung-Hong AU - Chung BH FAU - Garvey, W Timothy AU - Garvey WT FAU - Fu, Yuchang AU - Fu Y LA - eng GR - I01 CX000432/CX/CSRD VA/United States GR - R01 DK083562/DK/NIDDK NIH HHS/United States GR - DK-083562/DK/NIDDK NIH HHS/United States GR - R01 DK083562-04/DK/NIDDK NIH HHS/United States GR - DK-038764/DK/NIDDK NIH HHS/United States GR - P60-DK079626/DK/NIDDK NIH HHS/United States GR - P60 DK079626/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20111222 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - 0 (ADIPOQ protein, human) RN - 0 (ADIPOR1 protein, human) RN - 0 (ADIPOR2 protein, human) RN - 0 (APPL1 protein, human) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adiponectin) RN - 0 (Carrier Proteins) RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Lipoproteins, LDL) RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Adiponectin) RN - 0 (oxidized low density lipoprotein) RN - 0 (steroid receptor RNA activator, human) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/metabolism MH - Adiponectin/*metabolism MH - Atherosclerosis/genetics/immunology/*metabolism MH - Carrier Proteins/metabolism MH - Cell Line, Tumor MH - Cholesterol/metabolism MH - Cytokines/genetics/*metabolism MH - Foam Cells/immunology/*metabolism MH - Gene Expression Regulation MH - Humans MH - Inflammation/genetics/immunology/*metabolism MH - Inflammation Mediators/*metabolism MH - Lipoproteins, LDL/metabolism MH - NF-kappa B/metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA Interference MH - RNA, Messenger/metabolism MH - Receptors, Adiponectin/genetics/*metabolism MH - *Signal Transduction MH - Transfection PMC - PMC3288755 MID - NIHMS345889 COIS- Conflict of Interest: none declared EDAT- 2012/01/10 06:00 MHDA- 2012/06/13 06:00 PMCR- 2013/03/01 CRDT- 2012/01/10 06:00 PHST- 2010/12/16 00:00 [received] PHST- 2011/12/13 00:00 [revised] PHST- 2011/12/14 00:00 [accepted] PHST- 2012/01/10 06:00 [entrez] PHST- 2012/01/10 06:00 [pubmed] PHST- 2012/06/13 06:00 [medline] PHST- 2013/03/01 00:00 [pmc-release] AID - S0021-9150(11)01161-0 [pii] AID - 10.1016/j.atherosclerosis.2011.12.014 [doi] PST - ppublish SO - Atherosclerosis. 2012 Mar;221(1):66-75. doi: 10.1016/j.atherosclerosis.2011.12.014. Epub 2011 Dec 22.