Terpene Lactucopicrin Limits Macrophage Foam Cell Formation by a Reduction of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Lipid Rafts.

Abstract

Sustained inflammation promotes macrophage foam cell formation by promoting cholesterol influx and impairing cholesterol efflux. Terpene lactucopicrin, affluent in vegetables of the Asteraceae family (e.g., chicory, curly escarole, and lettuce) can inhibit atherogenesis in mice. However, it remains unknown whether and how lactucopicrin regulates macrophage foam cell formation. Lactucopicrin at physiologically reachable concentrations inhibits oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in inflammatory mouse bone marrow derived macrophages established by 50 pg mL-1 of LPS, reachable level in patients with metabolic endotoxemia. This effect is not due to modulation of cholesterol efflux, but reliant on a reduction in lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-mediated cholesterol influx. Mechanistically, lactucopicrin does not affect LOX-1 expression, cellular oxidative stress, and exocytosis, known mechanisms regulating LOX-1 function in cholesterol influx. Strikingly, lactucopicrin selectively decreases LOX-1 content in lipid rafts, an effect responsible for the lactucopicrin effect on cholesterol influx. Moreover, ApoE-/- mice fed a high fat diet supplemented with lactucopicrin for 12 weeks display fewer macrophage foam cells within atherosclerotic plaques relative to the control mice. Lactucopicrin limits macrophage foam cell formation through a reduction of LOX-1 distribution in lipid rafts, thus contributing to its atheroprotective effect.