Advisory Committee Chair
Timothy W Garvey
Advisory Committee Members
Etty N Benveniste
Stuart J Frank
Roger C White
Document Type
Dissertation
Date of Award
2010
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Macrophages play a critical role in the initiation and progression of atherosclerosis by producing pro-inflammatory mediators and transforming into lipid-laden foam cells. The prevention of lipid accumulation and inflammation in macrophage foam cells, therefore, represents a promising target for effective therapy for atherosclerosis. Adiponectin is a circulating cytokine primarily expressed and secreted by adipocytes, and is downregulated in obesity-linked diseases including type 2 diabetes, coronary artery disease and hypertension. In oxidized low-density lipoprotein (oxLDL)-induced human THP-1 macrophage foam cells, adiponectin suppresses lipid accumulation through decreasing lipid uptake and increasing high-density lipoprotein (HDL)-mediated lipid efflux. The potential mechanisms that adiponectin utilizes to reduce lipid accumulation in these cells include: activating the peroxisome proliferator-activated receptor gamma (PPARγ), liver X receptor (LXR) and ATP-binding cassette transporter A1 (ABCA1) signaling pathways which promote lipid efflux; decreasing scavenger receptor AI (SR-AI) which facilitates lipid uptake; and increasing hormone sensitive lipase (HSL) which increases lipid hydrolysis. Adiponectin also inhibits the expression of two pro-inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor alpha (TNFα) in macrophage foam cells. We further investigated the roles of two adiponectin receptors (AdipoR1 and AdipoR2) and their downstream adaptor protein APPL1 (adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1) in mediating adiponectin functions. Modulating the expression levels of AdipoR1 and AdipoR2 showed that both receptors are crucial for transducing adiponectin signals to suppress lipid accumulation for macrophage foam cell transformation. While AdipoR1 was required by adiponectin to suppress TNFα and MCP-1 gene expression; AdipoR2 served as the dominant receptor for adiponectin suppression of SR-AI and upregulation of interleukin-1 receptor antagonist (IL-1Ra) gene expression. Furthermore, knockdown of APPL1 significantly abrogated the adiponectin inhibitory functions for lipid accumulation, SR-AI and nuclear factor-κB (NF-κB) gene expression and Akt phosphorylation in macrophage foam cells. In current studies, we have provided novel evidence that adiponectin-adiponectin receptors-APPL1 is a key signaling axis in suppressing macrophage foam cell lipid accumulation and inflammation. Activation of this axis may serve as a potential therapeutic target for ameliorating macrophage lipid metabolic disorders associated with atherosclerosis.
Recommended Citation
Tian, Ling, "Roles of Adiponectin and Its Receptors in Foam Cell Transformation" (2010). All ETDs from UAB. 3144.
https://digitalcommons.library.uab.edu/etd-collection/3144