Regulation of Endogenous Apolipoprotein E Secretion by Macrophages

Abstract

Abstract-Apolipoprotein E has critical roles in the protection against atherosclerosis and is understood to follow the classical constitutive secretion pathway. Recent studies have indicated that the secretion of apoE from macrophages is a regulated process of unexpected complexity. Cholesterol acceptors such as apolipoprotein A-I, high density lipoprotein, and phospholipid vesicles can stimulate apoE secretion. The ATP binding cassette transporter ABCA1 is involved in basal apoE secretion and in lipidating apoE-containing particles secreted by macrophages. However, the stimulation of apoE secretion by apoA-I is ABCA1-independent, indicating the existence of both ABCA1-dependent and -independent pathways of apoE secretion. The release of apoE under basal conditions is also regulated, requiring intact protein kinase A activity, intracellular calcium, and an intact microtubular network. Mathematical modeling of apoE turnover indicates that whereas some pools of apoE are committed to either secretion or degradation, other pools can be diverted from degradation toward secretion. Targeted inhibition or stimulation of specific apoE trafficking pathways will provide unique opportunities to regulate the biology of this important molecule. Key Words: lipid and lipoprotein metabolism Ⅲ atherosclerosis pathophysiology Ⅲ mechanisms of atherosclerosis Ⅲ cell biology/structural biology Ⅲ cell signalling/signal transduction A polipoprotein E (apoE) is a 34-kDa protein that is produced and secreted by many cell types such as hepatocytes, smooth muscle cells, neuronal cells, and macrophages. As a constituent of plasma lipopoproteins, apoE directs movement of lipids from the periphery to the liver, where high affinity binding of apoE to the LDL receptor and other members of the LDL-receptor family facilitates uptake of the lipoprotein particles. A critical role for apoE in the protection against atherosclerosis was clearly established by the development of the apoE knockout mouse and subsequent studies which showed that macrophage-specific expression of apoE was antiatherogenic. 1,2 The mechanisms by which macrophage apoE is antiatherogenic may include stimulating the removal of excess cholesterol from macrophage foam cells, 3 as well as anti-inflammatory, 4 antiproliferative, 5 and immunomodulatory properties. 6,7 The regulation of the secretion of apoE from macrophages is thus of great importance to our understanding of the atherosclerotic process.The aim of this review is to describe the regulation of the secretion of apoE by macrophages, in light of recent observations indicating that its trafficking and secretion are under the control of signaling pathways. Although recycling of lipoprotein-derived apoE is referenced briefly for comparison, a detailed analysis of apoE recycling is beyond the scope of the present review and the interested reader is directed to recent excellent reviews on this topic. 8 -10 Basic Biology of ApoE in Macrophages Transcriptional Regulation of ApoE SynthesisTranscription of macrophage apoE can ...

Bilberries exert an anti-atherosclerotic effect in lipid-loaded macrophages

“…We demonstrate that BE induces a significant dose-dependent increase of secreted apoE associated with CETP secretion from lipid-loaded macrophages, a process that might be regulated by the inhibition of NF-κB and stimulation of PKA signaling in a dose-dependent manner. This effect is similar to the one demonstrated for lipidfree apoA-I and HDL 3 that stimulate both apoE and CETP secretion from lipid-loaded macrophages by the modulation of NF-κB and PKA signaling pathways [10,13,30].…”

“…Apolipoprotein (apo) E has been proposed as mediator for the cholesterol efflux from macrophages in the presence/absence of extracellular acceptors, including HDL 3 and lipidfree apoA-I [10]. Macrophages secrete cholesterylester transfer protein (CETP), which accounts for the enrichment of the triglyceride-rich apoB-containing lipoproteins with cholesteryl esters from HDL, but can also contribute to the reverse cholesterol efflux [11,12].…”

Changes in lipid metabolism during last month of pregnancy and first two months of lactation in primiparous cows – analysis of apolipoprotein expression pattern and changes in concentration of total cholesterol, HDL, LDL, triglycerides

“…Kockx et al (2008) stated that the secretion of apo E may be stimulated by apo A-1, apo A-IV and LDL, HDL. Worth noting is a reverse tendency for two analyzed parameters observed in our studies -an increase in apo E during lactation, and a decrease in triglyceride concentration.…”

Protein Kinase C Controls Vesicular Transport and Secretion of Apolipoprotein E from Primary Human Macrophages

“…ApoE mediates the clearance of triglyceride-rich lipoproteins, inhibits proliferation of smooth muscle cells and lymphocytes, contributes to antigen presentation, and promotes cholesterol efflux from foam cell macrophages (3)(4)(5)(6)(7)(8)(9). ApoE knock-out mice develop hyperlipidemia and severe atherosclerotic lesions (10,11).…”

“…It is known that newly synthesized apoE follows the classical secretory pathway, whereby it is trafficked into the endoplasmic reticulum, post-translationally glycosylated and sialylated in the Golgi network, and transported in vesicles to the plasma membrane for secretion (1,8,15,16) or reinternalization and resecretion or degradation (2,(17)(18)(19). ApoE secretion is a constitutive process controlled by the ATP-binding cassette transporter, ABCA1 (20,21).…”