Journal
JOURNAL OF LIPID RESEARCH
Volume 54, Issue 9, Pages 2315-2324Publisher
ELSEVIER
DOI: 10.1194/jlr.R039479
Keywords
adenosine triphosphate-binding cassette (ABC) transporter A1 and G1; apolipoprotein A-I, PDZK1; scavenger receptor class B, type I; high density lipoprotein
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Funding
- Crystal Charity Ball Center for Pediatric Critical Care Research
- Children's Medical Center Foundation
- Lowe Foundation
- Associates First Capital Corporation Distinguished Chair in Pediatrics at UT Southwestern
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High density lipoprotein (HDL) cholesterol has direct effects on numerous cell types that influence cardiovascular and metabolic health. These include endothelial cells, vascular smooth-muscle cells, leukocytes, platelets, adipocytes, skeletal muscle myocytes, and pancreatic beta cells. The effects of HDL or apoA-I, its major apolipoprotein, occur through the modulation of intracellular calcium, oxygen-derived free-radical production, numerous kinases, and enzymes, including endothelial nitric-oxide synthase (eNOS). ApoA-I and HDL also influence gene expression, particularly genes encoding mediators of inflammation in vascular cells. In many paradigms, the change in intracellular signaling occurs as a result of cholesterol efflux, with the cholesterol acceptor methyl-beta-cyclodextrin often invoking responses identical to HDL or apoA-I. The ABC transporters ABCA1 and ABCG1 and scavenger receptor class B, type I (SR-BI) frequently participate in the cellular responses. Structure-function relationships are emerging for signal initiation by ABCA1 and SR-BI, with plasma membrane cholesterol binding by the C-terminal transmembrane domain of SR-BI uniquely enabling it to serve as a sensor of changes in membrane cholesterol. Further investigation of the processes underlying HDL and apoA-I modulation of intracellular signaling will potentially reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health.
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