Abstract 597: Nobiletin Reduces Intestinal Lipoprotein Production in LDL Receptor-Null Mice With Diet-Induced Insulin Resistance

Insulin resistant subjects display excessive postprandial lipemia (PPL), defined by overproduction of intestinal triglyceride (TG)-rich, apoB48-containing chylomicrons (CM), which contribute to atherogenesis. However, the regulation of intestinal lipoprotein secretion by insulin and the mechanisms underlying elevated CM production in insulin resistant states remain poorly understood. In mice, the citrus flavonoid nobiletin prevents diet-induced obesity, dyslipidemia, insulin resistance, hepatic steatosis and VLDL overproduction. In the present study, we sought to characterize the aberrant PPL response in mice with diet-induced insulin resistance and hypothesized that nobiletin treatment would correct this abnormal response by normalizing intestinal insulin signaling and TG metabolism. Ldlr-/- mice were fed a high-fat, cholesterol-containing (HFHC) diet (42% fat, 0.2% cholesterol), a HFHC diet plus 0.3% w/w nobiletin or chow for 8 weeks (n=8 per group). Compared to chow, HFHC-fed mice displayed elevated TG (3-fold) within intestinal tissue following a 6 hour fast, which was completely normalized by nobiletin. Fasting-refeeding studies revealed impaired FoxO1 phosphorylation, increased mTOR phosphorylation and elevated Srebp1c mRNA in the jejunum of HFHC-fed mice, indicating intestinal insulin resistance. These parameters were normalized by nobiletin. Measurement of plasma TG following an oral gavage of 150ul olive oil revealed a 3-fold elevation in the total TG area under the curve, which was prevented by nobiletin. Intestinal CM production was determined by injection of mice with poloxamer-407 to inhibit plasma TG-rich lipoprotein lipolysis followed by a gavage containing olive oil and 3H-triolein. Although plasma TG was higher at baseline in HFHC-fed mice, no difference in secretion rates of TG mass or TG radioactivity was observed compared to nobiletin-treated or chow-fed mice. However, secretion of apoB48 was elevated by 20% in HFHC-fed mice, whereas nobiletin decreased apoB48 secretion to levels observed in chow-fed mice. These results indicate that nobiletin prevents intestinal TG accumulation and apoB48 overproduction induced by a HFHC diet, in part, through correction of intestinal insulin resistance.