Intestinal lymphatic HDL miR‐223 and ApoA‐I are reduced during insulin resistance and restored with niacin

The intestine is involved in whole-body lipid and cholesterol homeostasis and secretes lipoproteins containing apolipoprotein (Apo)B48 and discrete ApoA-I into the mesenteric lymph. The lymphatic system has been proposed to have a significant role in the reverse cholesterol transport pathway associated with HDL-ApoA-I. In conditions of insulin resistance (IR), there is intestinal overproduction of chylomicrons containing ApoB48; however, there is limited data on the intestinal synthesis and secretion of HDL-ApoA-I. microRNA (miR)-223 has been shown to regulate peripheral HDL metabolism and may impact intestinal-derived HDL. Niacin (nicotinic acid; vitamin B3) is known to regulate lipid metabolism, but the role of niacin in modulating intestinal lipid and lipoprotein (ApoB48 and ApoA-I) metabolism is unknown. The aim of this study was to determine the secretion of intestinal lymphatic HDL-ApoA-I and the effect of dietary intervention with niacin on these pathways in a rodent model of IR. HDL was isolated from intestinal mesenteric lymph by density ultracentrifugation, and subsequent HDL miR analysis was developed in collaboration with Exiqon Services. Insulin-resistant rodents were fed chow or chow with niacin (1% w/w) for 6 wk. Intestinal lymph HDL-ApoA-I and miR-223 expression were lower by at least 45 and 60%, respectively, and lymph HDL was associated with 85% higher triglyceride (TG) content in IR compared to non-IR control group. Niacin was found to increase secretion of lymph HDL and miR-223 by at least 50-60% and to deplete the TGs associated with HDL compared with the nontreated IR group. Niacin significantly increased peroxisome proliferator-activating nuclear receptor α and carnitine palmitoyltransferase I α mRNA and annulled Tnf-α mRNA expression in intestinal (jejunal) explants. Altered intestinal lymphatic HDL-ApoA-I and miR-223 metabolism in IR and modulation by niacin may provide insight into the intestinal-mediated regulation of the reverse cholesterol transport pathway.-Mangat, R., Borthwick, F., Haase, T., Jacome, M., Nelson, R., Kontush, A., Vine, D. F., Proctor, S. D. Intestinal lymphatic HDL miR-223 and ApoA-I are reduced during insulin resistance and restored with niacin.