Atherosclerotic vascular disease is a major cause of morbidity and death in diabetes, but the underlying mechanisms are poorly understood. Insulin resistance at the cellular level causes many of the complications of diabetes. In recent collaborative studies with the Tabas and Accili laboratories, we have shown that macrophages from insulin receptor (IR) deficient mice display defective insulin signaling, increased posttranscriptional expression of CD36 and SRA, increased uptake of modified LDL and increased susceptibility to apoptosis induced by FC loading and other stimuli. Apoptotic susceptibility is related to a failure to induce Akt activity during the ER stress response. Accordingly, bone marrow transplantation from IR deficient mice into LDLR-/- mice results in formation of advanced lesions containing increased numbers of apoptotic macrophages and larger necrotic cores. In a converse model, LDLR-/- mice with peripheral IR deficiency and increased signaling through preserved hepatic IRs, were found to have lower VLDL/LDL levels and decreased atherosclerosis. The underlying hypothesis of this project is that insulin resistance worsens atherosclerosis, acting both at the level of the vessel wall, and also in the liver. The proposal will seek to further evaluate mechanisms linking insulin resistance in macrophage foam cells to atherosclerosis, and also the relationship between insulin signaling in the liver and alterations in lipoprotein metabolism.
In Aim 1 we will collaborate to investigate the mechanisms and consequences of increased apoptosis in macrophages with defective insulin signaling. In particular we will determine if decreased IR signaling and lower Akt activity leads to increased nuclear FoxO1/3 activity, increased ER stress/CHOP induction and apoptosis.
In Aim 2 we will extend our in vivo studies and further explore the hypothesis that defective insulin signaling in lesional macrophages increases macrophage apoptosis and atheroma complexity. Related studies in Projects 1 and 3 will test the role of SRA and FoxOs in mediating these effects.
In Aim 3 we will determine if increased hepatic insulin signaling leads to decreased hepatic FoxO1 activity and thus increased apoB degradation within the secretory pathway. These experiments complement those of Project 3 examining the impact of hepatic FoxO1 overexpression on hepatic lipid and lipoprotein metabolism. This project may provide new molecular insights into the causes of diabetic dyslipidemia and its vascular complications.
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