Abstract 629: Niacin Beneficially Alters the Secretion of Intestinal HDL in a Rat Model of Insulin Resistance by Opposing Effects on PPAR Alpha and TNF Alpha

Abstract

INTRODUCTION: Niacin is the oldest hypolipidemic drug that effectively lowers plasma triglycerides whilst increasing HDL-C concentration. However the mechanism of action of niacin still remains elusive. Emerging evidence shows that in addition to the liver, the intestine also contributes to whole body HDL metabolism. The effect of insulin resistance and niacin on intestinal HDL secretion is unclear. OBJECTIVE: To determine the effect of niacin on the secretion and composition of intestinal lymphatic HDL in a model of insulin resistance (JCR:LA-cp rat). METHODS: Insulin resistant (IR) rats were fed control chow or chow supplemented with niacin (1% w/w) for 6 weeks. The mesenteric lymph duct was cannulated and lymph sampled following an intra-gastric intralipid (fed) infusion for 6 hrs. The lymphatic HDL (1.063-1.21g/ml) fraction was separated by density ultracentrifugation; associated lipid and protein composition was analyzed. Primary enterocytes were isolated by an adaptation of the Wieser method. Jejunal explants from IR rats were treated with 5mg/ml niacin or nicotinamide and mRNA expression was assessed. RESULTS: In IR rats, apo-AI lymphatic HDL secretion was reduced (-47%), but associated TG content enriched (86%), compared to non-IR rats. Interestingly, niacin was found to stimulate the secretion of lymph HDL (>60%) compared to non-treated IR rats. Niacin treatment also normalized the TG content of lymphatic HDL particles. In parallel experiments, niacin was also shown to beneficially reduce lymphatic apoB secretion, suggesting concomitant pathways. Primary enterocytes isolated from niacin treated animals had increased ABCA1 and PPAR alpha mRNA compared to untreated control. Further, niacin (but not nicotinamide) significantly increased PPAR alpha and CPT1a mRNA, while annulling TNF alpha mRNA in treated jejunal explants. Conversely, there was no effect of niacin or nicotinamide treatment on ATGL, PLIN2 or ATG5. CONCLUSION: Insulin resistance may reduce the secretion of apoAI HDL into mesenteric lymph, potentially contributing to particle dysfunction. Niacin may contribute to improving CVD risk by restoring the number and TG enrichment of intestinal apoAI particles.