| Diabetes has become an epidemic, and it is estimated that by the year 2020, diabetes will affect 250 million people worldwide. Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in patients with Type 2 diabetes. In early atherogenesis, monocytes are recruited to the endothelium, where they migrate into the subendothelial space and differentiate into macrophages. Macrophages in an atherosclerotic plaque have the ability to take up oxidized lipoproteins and form "foam cells." Differentiated macrophages also have the ability to upregulate members of the ATP-binding cassette transporter family, namely ABCA1 and ABCG1, to facilitate removal of sterol from the cell. ABCG1 is a novel ABC transporter that is ubiquitously expressed and is a primary regulator of cholesterol efflux to HDL in reverse cholesterol transport. 12/15-lipoxygenase (12/15LO) is a non-heme iron containing dioxygenase that incorporates molecular oxygen stereospecifically into arachidonic or linoleic acids to produce fatty acid hydroxy-derivatives. The 12/15LO pathway is upregulated in the pathogenesis of atherosclerosis and diabetes. Here, we show that macrophages overexpressing 12/15LO have reduced cholesterol efflux to HDL due to a reduction in ABCG1 protein expression. 12/15LO enhances the degradation and serine phosphorylation of ABCG1, ultimately targeting the transporter to the proteasome. 12/15LO activates the p38 and JNK2 MAPK pathways to phosphorylate ABCG1 on serine residues and enhance protein turnover of the transporter. These studies identified novel regulation of ABCG1 and cellular cholesterol metabolism, and strategies to upregulate ABCG1 expression and function could have important implications to limit vascular disease, particularly in the setting of Type 2 diabetes. |
