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HDL activates expression of genes stimulating cholesterol efflux in human monocyte-derived macrophages.
- Source :
-
Experimental and molecular pathology [Exp Mol Pathol] 2018 Oct; Vol. 105 (2), pp. 202-207. Date of Electronic Publication: 2018 Aug 16. - Publication Year :
- 2018
-
Abstract
- High density lipoproteins (HDL) are key components of reverse cholesterol transport pathway. HDL removes excessive cholesterol from peripheral cells, including macrophages, providing protection from cholesterol accumulation and conversion into foam cells, which is a key event in pathogenesis of atherosclerosis. The mechanism of cellular cholesterol efflux stimulation by HDL involves interaction with the ABCA1 lipid transporter and ensuing transfer of cholesterol to HDL particles. In this study, we looked for additional proteins contributing to HDL-dependent cholesterol efflux. Using RNAseq, we analyzed mRNAs induced by HDL in human monocyte-derived macrophages and identified three genes, fatty acid desaturase 1 (FADS1), insulin induced gene 1 (INSIG1), and the low-density lipoprotein receptor (LDLR), expression of which was significantly upregulated by HDL. We individually knocked down these genes in THP-1 cells using gene silencing by siRNA, and measured cellular cholesterol efflux to HDL. Knock down of FADS1 did not significantly change cholesterol efflux (p = 0.70), but knockdown of INSIG1 and LDLR resulted in highly significant reduction of the efflux to HDL (67% and 75% of control, respectively, p < 0.001). Importantly, the suppression of cholesterol efflux was independent of known effects of these genes on cellular cholesterol content, as cells were loaded with cholesterol using acetylated LDL. These results indicate that HDL particles stimulate expression of genes that enhance cellular cholesterol transfer to HDL.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- ATP Binding Cassette Transporter 1 genetics
Atherosclerosis physiopathology
Biological Transport
Cholesterol
Cholesterol, HDL metabolism
Delta-5 Fatty Acid Desaturase
Fatty Acid Desaturases genetics
Fatty Acid Desaturases metabolism
Foam Cells
Gene Expression Profiling
Gene Expression Regulation genetics
Gene Silencing
Humans
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Lipoproteins, HDL genetics
Lipoproteins, HDL metabolism
Macrophages metabolism
Membrane Proteins genetics
Membrane Proteins metabolism
RNA, Messenger
RNA, Small Interfering
Receptors, LDL genetics
Receptors, LDL metabolism
THP-1 Cells
Up-Regulation
Cholesterol, HDL genetics
Macrophages physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0945
- Volume :
- 105
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental and molecular pathology
- Publication Type :
- Academic Journal
- Accession number :
- 30118702
- Full Text :
- https://doi.org/10.1016/j.yexmp.2018.08.003