Bioactive lipid metabolism by carboxylesterase 1 (CES1) in macrophages (LB154)

Abstract

Human carboxylesterases (CES) have an emerging role in lipid metabolism. CES1 in macrophages is a hydrolase with broad endogenous substrate specificity, including cholesteryl ester, triacylglycerol, and 2‐arachidonoylglycerol (2‐AG), which may be relevant to cardiovascular disease and other pathologies related to lipid metabolism dysfunction. 2‐AG is an endogenous ligand of the cannabinoid receptors (CB1 and CB2) which are involved in the regulation of numerous processes, including lipogenesis, inflammation, and cholesterol flux in macrophages. To characterize the cholesterol homeostatic functions of CES1, its expression was stably knocked‐down in a THP‐1 monocyte/macrophage line (CES1KD/THP‐1) and the extent of in situ 2‐AG catabolism and cholesterol uptake and efflux from foam cells was evaluated. Expression levels of several genes involved in cholesterol and 2‐AG homeostasis were also determined. Perturbation of CES1 function altered in situ 2‐AG levels as well as the expression of multiple genes involved in cholesterol uptake and metabolism through both compensatory upregulation (CES3) and downregulation (ABCA1, CYP27A1, CD36, SRA) mechanisms. CES1KD/THP‐1 foam cells exhibited altered free and esterified cholesterol mass compared to control cells, whereas cholesterol efflux was unchanged. These finding suggest a complex central role for CES1 in macrophage cholesterol homeostasis.Grant Funding Source: Supported by NIH 1R15ES015348‐02