Abstract
Hypolipidemic effects of niacin (nicotinic acid) include lowering plasma triglycerides (TG) 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 (IR) and niacin on intestinal HDL secretion is not known. Therefore the objective of this study was to determine the effect of niacin on the secretion, composition and miRNA profile of intestinal lymphatic HDL in a model of insulin resistance (IR) (JCR:LA-cp rat). 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, protein and miRNA composition was analyzed. For ex-vivo experiments, Jejunal explants from IR rats were treated with 5mg/ml niacin or nicotinamide and mRNA expression was assessed. In IR rats, apo-AI lymphatic HDL secretion was reduced (-47%) and associated with an enriched (86%) TG content, compared to non-IR rats. Interestingly, niacin was found to stimulate the secretion (number) of lymph HDL (>60%), as well as depleting the TG content compared to non-treated IR rats. Niacin (but not nicotinamide) significantly increased PPAR alpha and cpt1a mRNA, and annulled TNF alpha mRNA in jejunal explants. In lymph associated HDL from IR rats, miR223 and miR29c were both decreased compared to control. Interestingly niacin treatment increased both miR223 and miR29c in lymph associated HDL, suggesting a benefit to restore anti-inflammatory action of miR223 as well as the collagen/fibrotic repair functions of miR29c. IR may reduce the secretion of apoAI HDL into mesenteric lymph, potentially contributing to lipid enrichment and particle dysfunction. Niacin may contribute to improving CVD risk by increasing the number of lipid depleted intestinal apoAI particles. The ability of niacin to modulate miRs in the lymphatic HDL fraction may provide novel insight into hypolipidemic mechanisms of action of niacin.
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