Abstract 5546: Anti-Inflammatory Effects of Nicotinic Acid: Suppression of Fractalkine, RANTES, and MCP-1 and Upregulation of Adiponectin in 3T3-L1 Adipocytes

Abstract

Introduction: The atheroprotective effects of nicotinic acid (NA) may be mediated through well-defined effects on plasma lipoproteins. However, a major site of action for nicotinic acid is adipose tissue, via the G-protein coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to the systemic inflammatory process associated with cardiovascular disease, we hypothesized that: NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin. Methods and Results: 3T3-L1 pre-adipocytes were differentiated into adipocytes using insulin and dexamethasone (10 −7 M) for 10 days. Adipocytes were incubated with NA (10 −6 M to 10 −3 M) under basal conditions, and/or with TNFα (1.0 ng/ml for 4 hours) to provoke inflammation. Quantitative real-time PCR for mRNA showed increased fractalkine (CX3CL1) (9-fold ± 3.3: P < 0.01), monocyte chemoattractant protein-1 (MCP-1) (24-fold ± 1.2: P < 0.001), and RANTES (CCL5) (500-fold ± 55: P < 0.001) in response to TNFα treatment (n=6). The addition of nicotinic acid (10 −4 M) to TNFα treated adipocytes attenuated expression of CXCL3 (50 ±12%: P < 0.01); MCP-1 (50 ± 6%: P < 0.01) and CCL5 (70 ± 3%: P < 0.01). By contrast, NA, (10 −6 M to 10 −3 M) increased in a dose-dependent manner mRNA of the atheroprotective hormone adiponectin (3- to 5-fold n=6, P <0.01 after 4 hours) and protein expression (2-fold) after 24 hours (n=4, P < 0.05). Conclusions: NA directly suppresses pro-atherogenic chemokines and promotes secretion of atheroprotective adiponectin by adipocytes. This is the first report of fracktalkine expression by adipose tissue. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new “pleiotropic” role for NA.