Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans

Angiopoietin-like 4 (ANGPTL4) is a regulator of LPL activity. In this study we examined whether different fatty acids have a differential effect on plasma ANGPTL4 levels during hyperinsulinemia in healthy lean males. In 10 healthy lean males, 3 hyperinsulinemic euglycemic clamps were performed during concomitant 6 h intravenous infusion of soybean oil (Intralipid® rich in PUFA), olive oil (Clinoleic® rich in MUFA) and control saline. In 10 other healthy lean males, 2 hyperinsulinemic clamps were performed during infusion of a mixed lipid emulsion containing a mixture of fish oil (FO), medium-chain triglycerides (MCTs), and long-chain triglycerides (LCTs) (FO/MCT/LCT; SMOFlipid®) or saline. FFA levels of approximately 0.5 mmol/l were reached during each lipid infusion. Plasma ANGPTL4 decreased during hyperinsulinemia by 32% (18-52%) from baseline. This insulin-mediated decrease in ANGPTL4 concentrations was partially reduced during concomitant infusion of olive oil and completely blunted during concomitant infusion of soybean oil and FO/MCT/LCT. The reduction in insulin sensitivity was similar between all lipid infusions. In accordance, incubation of rat hepatoma cells with the polyunsaturated fatty acid C22:6 increased ANGPTL4 expression by 70-fold, compared with 27-fold by the polyunsaturated fatty acid C18:2, and 15-fold by the monounsaturated fatty acid C18:1. These results suggest that ANGPTL4 is strongly regulated by fatty acids in humans, and is also dependent on the type of fatty acid.