Modulation of lipoprotein metabolism and atherosclerosis by the G protein-coupled receptor, G2A

Abstract

The G protein-coupled receptor, G2A, is expressed by multiple cell-types involved in atherosclerosis and is activated by structurally related lysophospholipids generated during low-density lipoprotein (LDL) oxidation and cholesterol esterification on circulating high-density lipoprotein (HDL) particles. In vitro studies have demonstrated that G2A mediates multiple biological responses relevant to atherosclerosis, including macrophage chemotaxis and apoptosis. To determine the role of these G2A-mediated effects in atherosclerosis, we generated hypercholesterolemic G2A deficient (G2A-/-) and G2A sufficient (G2A+/+) LDL receptor knockout (LDLR-/-) mice, a commonly used hypercholesterolemic model of atherogenesis. Although G2A deficiency resulted in slight reductions in lesional macrophage apoptosis at the aortic root without affecting lesion size during early stages of atherogenesis, the major impact of G2A deletion throughout the entire aorta at early and later stages of atherogenesis was a robust reduction in lesion size. Although consistent with the loss of G2A chemotactic function, suppression of atherosclerosis in G2A-/-LDLR-/- mice was associated with increased circulating numbers of apolipoprotein E (apoE)-containing HDL particles. The ability of G2A inactivation to raise HDL in hypercholesterolemic LDLR-/- mice was dependent on apoE expression. In addition, G2A deletion failed to raise HDL levels in apoE knockout (apoE-/-) mice and consequently did not suppress atherosclerosis, irrespective of gender or the type of diet intervention. Hepatocytes, the primary cell-type responsible for HDL biogenesis, were found to express G2A and hepatocytes from hypercholesterolemic G2A-/-LDLR-/- mice secreted significantly more apoE-containing HDL particles compared to those from their G2A+/+LDLR-/- counterparts. This occurred in the absence of any significant alterations in the expression of genes encoding apoE and other key regulators of HDL metabolism. Collectively, these studies demonstrate that G2A-mediated chemotaxis does not play a role in vivo during atherogenesis and establish a novel apoE-dependent mechanism mediated by G2A to control HDL biogenesis that is required for the pro-atherogenic action of G2A.