Sterol regulation of immunometabolic responses in cardiometabolic diseases

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY Alterations in the control of lipid homeostasis can lead to cardiometabolic diseases, including atherosclerosis, the most common cause of mortality in Western societies. Cellular cholesterol homeostasis significantly contributes to the chronic inflammation observed in atherosclerotic lesions, suggesting that the immunometabolic modulation of pathological processes associated to atherosclerosis might represent the next frontier in management cardiovascular diseases CVD). Work from our laboratory has recently elucidated the key role of cholesterol biosynthetic intermediates (desmosterol and lanosterol) and cholesterol derivatives [25-hydroxycholesterol (25-HC)] as emergent immune regulators of macrophages in response to lipid overloading and innate immune activation. Our preliminary data and previous studies demonstrated that desmosterol is the major ligand of liver X receptor (LXR) in macrophages, modulating cholesterol metabolism and inflammatory responses in foamy macrophages. Notably, macrophage overexpression of DHCR24, the enzyme that catalyses the conversion of desmosterol to cholesterol, reduces cellular desmosterol levels and promotes atherosclerosis. In this proposal, we will determine whether the genetic deletion of DHCR24 in macrophages attenuates the progression of atherosclerosis and define the contribution of LXR in this process (Aim 1). We will test the hypothesis that hepatocyte specific genetic deletion or pharmacological inhibition of DHCR24 will increase circulating and vascular desmosterol levels, decreasing vascular inflammation and protecting against the progression of atherosclerosis (Aim 2). These studies will exploit novel animal models allowing the macrophages and hepatocyte genetic deletion of Dhcr24 and Lxrab and cutting-edge technologies (genomics and metabolomics) to evaluate the potential therapeutic efficacy of increasing desmosterol levels in macrophages for treating cardiometabolic diseases.