Impact of Myeloid ACAT1 Depletion on the Progression of Atherosclerosis and Xanth

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DESCRIPTION (provided by applicant): Cardiovascular disease is a public health issue and continues to be a challenging epidemic in the U.S. Mounting evidence suggests that atherosclerosis is a high risk factor for dyslipidemic cardiovascular disease. To offer opportunities for therapeutic intervention, it is important to understand the patho-physiological pathways involved in atherosclerosis. This application focuses on determining the mechanisms which drive foam cell formation in atherosclerotic lesions. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) has surfaced as a potential target for atherosclerosis treatment, likely due its catalytic activity which involves conversion of free cholesterol into cholesterol esters. Cholesterol esters are major components of lipid droplets in macrophage foam cells. Research conducted to test whether inhibiting ACAT1 can prevent atherosclerosis in animal models resulted in conflicting opinions regarding its benefits. This controversy stems from reports of pharmacological inhibition of ACAT1 resulting in improvement of plaque stability, while inhibiting ACAT1 by global Acat1 knockout (Acat1-/-) resulted in no change in plaque size. Alterations in plaque morphology were speculated to be attributed to the lack of ACAT1 in macrophages. However, recently our laboratory has shown that global Acat1 knockout (KO) impacts expression of ACAT1 in multiple tissues and cell types, including cells in the hematopoietic stem cell lineage. Alterations in hematopoietic stem cells can result in leukocytosis, which is a risk factor for atherosclerosis. Therefore, global Acat1 KO may produce many unknown effects and consequences. The role of macrophage ACAT1 in atherosclerosis remains to be clarified. The work proposed in Aim 1 is designed to address this issue by using a novel mouse line recently created in our laboratory, (Acat1-M-M), as a tool to examine the impact of myeloid ACAT1 depletion on atherosclerosis progression. We will characterize and compare plaque formation and morphology in early and late stage atherosclerotic lesions between the Apoe-/-, Apoe-/-/Acat1-/- and the Apoe-/-/Acat1-M-M mice fed an atherogenic diet. Previously it was shown that global Acat1 KO under a hypercholesterolemic metabolic state (i.e. under an Apoe deficient or low density lipoprotein receptor deficient background) results in accelerated growth of xanthoma lesions, which arise when free cholesterol builds up in the subcutaneous layer of the dermis. This adverse effect was speculated to be attributed to the lack of ACAT1 in macrophages. In aim 2, we propose to test the validity of this interpretation by using the Apoe-/- /Acat1-M-M mice to study the effects of macrophages specific deletion of ACAT1 on the progression of xanthomatosis.