Abstract
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 β 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-β-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.
Highlights
High density lipoprotein (HDL) cholesterol has direct effects on numerous cell types that influence cardiovascular and metabolic health
This review highlights recent advances in our knowledge of HDL-initiated processes mediated by changes in intracellular signaling in numerous cell types of relevance to both cardiovascular and metabolic conditions, which represent actions of the lipoprotein beyond its classical role in global cholesterol homeostasis
Responses to HDL or to apoA-I, its major apolipoprotein, in cellular targets directly involved in vascular biology will be reviewed, followed by a summary of the mechanisms that HDL influences in cell types participating in energy and glucose homeostasis
Summary
G proteins p38 MAP kinase Rho kinase Ras p42/44 MAP kinase Rac GTPase Src kinase AMPK. (67), [91] [49], [55] [49], [87] [49], [84], [108] [55] [57], [67] [24], [56] [56], [67] [35], [37], [62]
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