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06:46
Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages
Published on: June 30, 2016
Cellular sphingolipids regulate macrophage apolipoprotein E secretion.
Danijela Lucic1, Zhi Hua Huang, DeSheng Gu
1Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Biochemistry
|September 1, 2007
Summary
Cellular sphingolipids regulate apolipoprotein E (apoE) secretion from macrophages. Increased ceramide reduces apoE secretion, while reduced sphingomyelin (SM) impairs secretion and increases apoE retention, impacting atherosclerosis risk.
Area of Science:
- Lipid metabolism
- Cell biology
- Atherosclerosis research
Background:
- Macrophage-derived apolipoprotein E (apoE) plays a critical role in the vessel wall's response to atherogenic injury.
- Understanding the regulation of apoE secretion is crucial for developing strategies to combat atherosclerosis.
Purpose of the Study:
- To investigate a novel post-transcriptional pathway regulating apoE secretion from macrophages.
- To elucidate the role of cellular sphingolipids, specifically ceramide and sphingomyelin (SM), in apoE handling.
Main Methods:
- J774 macrophages expressing human apoE3 cDNA were treated with sphingomyelinase, or agents affecting ceramide and SM levels.
- Sphingolipid metabolism was manipulated by inhibiting synthesis or degradation.
- ApoE secretion and cellular retention were measured.
- A Chinese hamster ovary (CHO) cell model with altered sphingolipid synthesis was utilized.
Main Results:
- Treatment with sphingomyelinase or increased cellular ceramide reduced apoE secretion without increasing cellular retention.
- Inhibition of sphingomyelin (SM) synthesis decreased apoE secretion and increased its cellular retention, dependent on apoE's C-terminal domains.
- ApoE expression increased SM secretion, with SM co-localizing with apoE in secreted particles.
- Experiments in CHO cells confirmed the role of cellular sphingolipids in apoE secretion.
Conclusions:
- Cellular sphingolipids, ceramide and SM, significantly influence the post-transcriptional processing and secretion of nascent apoE by macrophages.
- Increased cellular ceramide appears to enhance apoE degradation, while reduced SM levels impede apoE secretion and promote intracellular retention.
- These findings suggest a model where SM content in intracellular membranes modulates apoE secretion via interactions with its lipid-binding domains, offering new insights into atherosclerosis regulation.
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