Insulin down-regulates specific activity of ATP-binding cassette transporter A1 for high density lipoprotein biogenesis through its specific phosphorylation

Insulin resistance/hyperinsulinism is one of the major risks for atherosclerotic vascular diseases and low HDL may be involved in pathogenesis. We examined direct effects of insulin on HDL biosynthesis focusing on the activity of ATP-binding cassette transporter A1 (ABCA1) in culture cells and in experimental animals. Insulin impairs HDL biosynthesis through modulation of ABCA1 activity by two different mechanisms. Insulin enhances degradation of ABCA1. However, even after this effect was cancelled by blocking its specific signal, insulin still reduces HDL biogenesis. This effect was found due to phosphorylation of ABCA1 that leads to decrease of its specific activity. We identified a novel insulin-specific phosphorylation site Tyr1206 of ABCA1 to regulate its specific activity. The observation in a rat model of insulin resistance was consistent with these results. The findings demonstrate a new mechanism for regulation of ABCA1 activity and provide new insights into the link between development of atherosclerosis, and insulin resistance/hyperinsulinism.