Investigate the function and consequent effects of CEBPD in polarized macrophages and pathogenesis of atherosclerosis

  • 賴 弘岳

Student thesis: Doctoral Thesis

Abstract

Atherosclerosis is an inflammatory disease driven by hyperlipidemia There are accumulating evidences to support that inflammation and lipid homeostasis are closely linked Macrophages mediate innate immune responses and lipid homeostasis and act as a key player in atherosclerosis However the cross talk among these processes in the development and progression of atherosclerosis are not fully defined For the past few years our recent studies successfully demonstrated the important role of the transcription factor CCAAT/enhancer-binding protein delta (CEBPD) in inflammation and cancer microenvironment over macrophages In this current study we aimed to dissect whether CEBPD functions at the junction of inflammation and macrophage lipid homeostasis We found that CEBPD colocalized with macrophages in human and mouse atherosclerotic plaques and that Cebpd deficiency in bone marrow cells suppressed atherosclerotic lesions in hyperlipidemic Apoe-/- mice In response to modified LDL the p38MAPK/CREB pathway contributed to CEBPD activation which promoted lipid accumulation in M1 macrophages but not in M2 macrophages The underlying mechanisms involved in this process included an increase in pentraxin 3 (PTX3)-mediated macropinocytosis of LDL and a reduction in ATP-binding cassette subfamily A member 1 (ABCA1)-mediated cholesterol efflux Also we found that ZNF202 mediates CEBPD-repressed ABCA1 gene transcription In addition we found that simvastatin (a HMG-CoA reductase inhibitor) can target CEBPD to block lipid accumulation in M1 macrophages In conclusion this study underscores the importance of cross talk between inflammation and lipid homeostasis and provides new insight into targeting macrophage phenotypes and functions in cardiovascular diseases
Date of Award2017 Jul 24
Original languageEnglish
SupervisorJu-Ming Wang (Supervisor)

Cite this

Investigate the function and consequent effects of CEBPD in polarized macrophages and pathogenesis of atherosclerosis
弘岳, 賴. (Author). 2017 Jul 24

Student thesis: Doctoral Thesis