Adiponectin reduces lipid accumulation in macrophage foam cells

Abstract

Adiponectin is one of several, important metabolically active cytokines secreted from adipocytes. Low circulating levels of this adipokine have been associated epidemiologically with obesity, insulin resistance, type II diabetes, and cardiovascular disease. To determine if adiponectin can modulate lipid metabolism in macrophages, we expressed the adiponectin gene in human THP-1 macrophage foam cells using a lentiviral vector expression system and demonstrated that macrophages transduced with the adiponectin gene had decreased lipid accumulation compared with control macrophages transduced with the LacZ gene. Macrophages transduced with the adiponectin gene also exhibited decreased oxidized low-density lipoprotein (oxLDL) uptake and increased HDL-mediated cholesterol efflux. Additional studies suggest two potential mechanisms for the reduced lipid accumulation in these adiponectin-transduced macrophage foam cells. The first mechanism involves the PPARgamma and LXR signaling pathways which up-regulate the expression of ABCA1 and promote lipid efflux from these cells. The second mechanism involves decreased lipid uptake and increased lipid hydrolysis which may result from decreased SR-AI and increased SR-BI and HSL gene activities in the transformed macrophage foam cells. We also demonstrated that the expression of two proatherogenic cytokines, MCP-1 and TNFalpha, were decreased in the adiponectin-transduced macrophage foam cells. These results suggest that adiponectin may modulate multiple pathways of lipid metabolism in macrophages. Our studies provide new insights into potential mechanisms of adiponectin-mediated alterations in lipid metabolism and macrophage foam cell formation which may impact the development of atherosclerosis.

The expression of ATP-binding cassette transporter A1 in Chinese overweight and obese patients

“…Furthermore, we also found that the reduction of ABCA1 in overweight and obese patients was related to lower circulating level of the antiatherogenic adipokine adiponectin, but not associated with higher levels of the proatherogenic adipokines leptin and resistin. This is in keeping with data from in vitro experiments and animal studies showing that adiponectin can upregulate ABCA1 expression and cholesterol efflux from macrophages, [11][12] and knockout adiponectin can decrease the expression of ABCA1. 12 The activation of peroxisome proliferator-activated receptor g (PPARg) and liver X receptor a (LXRa) is the major mechanism through which macrophage ABCA1 and ABCG1 expression can be upregulated.…”

“…[9][10] Concerning macrophage RCT, in vitro experiments have shown that adiponectin can upregulate the expression of ABCA1 and cholesterol efflux from human macrophages. [11][12] In adiponectin knockout mice, the expression of ABCA1 and cholesterol efflux from macrophages is decreased compared with wild-type mice. 12 However, whether adiponectin may influence ABCG1 and SR-BI is unclear, and few studies about the effects of adiponectin on cholesterol efflux from macrophages in humans have been carried out.…”

Annexin A6 is highly abundant in monocytes of obese and type 2 diabetic individuals and is downregulated by adiponectin in vitro

“…Most interestingly, adiponectin strongly induces ABCA1 expression in monocytes, indicating that higher ABCA1 levels are atheroprotective and contribute to enhance cholesterol removal from cells (Tsubakio-Yamamoto et al, 2008). In support of this hypothesis, lentiviral overexpression of adiponectin in macrophages reduces lipid accumulation and enhances cholesterol efflux to apolipoprotein A-I (Tian et al, 2009). In contrast, adiponectin-deficient mice show a significant reduction in ABCA1 and ABCG1 expression which correlates with a decreased cholesterol efflux to apolipoprotein A-I and to a minor extend to HDL, respectively (Tsubakio-Yamamoto et al, 2008).…”

“…Some of its atheroprotective features appear to affect cholesterol homeostasis in peripheral cells, as adiponectin reduces lipid accumulation and, stimulates reverse cholesterol transport in macrophages (Tsubakio-Yamamoto et al, 2008;Tian et al, 2009). Most interestingly, adiponectin strongly induces ABCA1 expression in monocytes, indicating that higher ABCA1 levels are atheroprotective and contribute to enhance cholesterol removal from cells (Tsubakio-Yamamoto et al, 2008).…”

Impact Of Adiponectin Overexpression On Allergic Airways Responses In Mice

“…Adiponectin decreases the ability of LPS or Toll-like receptor activation to elicit TNF and IL-6 production from macrophages [21][22][23][24] and reduces eotaxin expression in bone marrow derived macrophages stimulated with TNF and IL-4 [12]. Adiponectin also inhibits the transformation of macrophages to foam cells [25], which may explain the antiatherosclerotic effects of adiponectin. Cultured alveolar macrophages from adiponectin deficient mice demonstrate increased production of TNF , both innately and upon stimulation with LPS [26].…”