The Induction of Cytokine Release in Monocytes by Electronegative Low-Density Lipoprotein (LDL) Is Related to Its Higher Ceramide Content than Native LDL

Montserrat Estruch,Lorea Beloki,Jose Sanchez-Quesada,Jordi Ordoñez-Llanos,Sonia Benitez

doi:10.3390/ijms14022601

Abstract

Electronegative low-density lipoprotein (LDL(−)) is a minor modified LDL subfraction that is present in blood. LDL(−) promotes inflammation and is associated with the development of atherosclerosis. We previously reported that the increase of cytokine release promoted by this lipoprotein subfraction in monocytes is counteracted by high-density lipoprotein (HDL). HDL also inhibits a phospholipase C-like activity (PLC-like) intrinsic to LDL(−). The aim of this work was to assess whether the inhibition of the PLC-like activity by HDL could decrease the content of ceramide (CER) and diacylglycerol (DAG) generated in LDL(−). This knowledge would allow us to establish a relationship between these compounds and the inflammatory activity of LDL(−). LDL(−) incubated at 37 °C for 20 h increased its PLC-like activity and, subsequently, the amount of CER and DAG. We found that incubating LDL(−) with HDL decreased both products in LDL(−). Native LDL was modified by lipolysis with PLC or by incubation with CER-enriched or DAG-enriched liposomes. The increase of CER in native LDL significantly increased cytokine release, whereas the enrichment in DAG did not show these inflammatory properties. These data point to CER, a resultant product of the PLC-like activity, as a major determinant of the inflammatory activity induced by LDL(−) in monocytes.

Highlights

IntroductionModification of LDL is directly related to the initiation and progression of atherosclerosis
Modification of LDL is directly related to the initiation and progression of atherosclerosis.Modified LDL can promote subendothelial accumulation of cholesterol and activates the chronic inflammatory response characteristic of atheromatous lesions [1]
It has been suggested that it could be related to other atherogenic traits of LDL(−) [7], such as increased susceptibility to aggregation [8], abnormal apolipoprotein B conformation [9] or high binding to proteoglycans [10]

Summary

Introduction

Modification of LDL is directly related to the initiation and progression of atherosclerosis. Modified LDL can promote subendothelial accumulation of cholesterol and activates the chronic inflammatory response characteristic of atheromatous lesions [1]. Has some potentially atherogenic characteristics compared to native LDL. LDL(−) presents a phospholipase C (PLC)-like activity [6], whose origin is still unknown. It has been suggested that it could be related to other atherogenic traits of LDL(−) [7], such as increased susceptibility to aggregation [8], abnormal apolipoprotein B (apoB) conformation [9] or high binding to proteoglycans [10]. LDL(−) promotes the release of cytokines, including MCP1, IL6, IL8, IL10 and GRO, in endothelial cells [11], monocytes and lymphocytes [12,13]

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