Regulation of signal transduction by HDL

Abstract

which HDL serves to shuttle cholesterol from peripheral tissues or cells to the liver. 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. The evidence that HDL infl uences cardiovascular and metabolic health and disease will fi rst be briefl y summarized. Responses to HDL or to apoA-I, its major apolipoprotein, in cellular targets directly involved in vascular biology will then be reviewed, followed by a summary of the mechanisms that HDL infl uences in cell types participating in energy and glucose homeostasis. The processes underlying apoA-I-or HDL-induced changes in intracellular signaling will then be discussed, and fi nally presently unanswered questions in this realm of HDL biology will be considered. Although HDL cargo molecules can contribute to cellular responses to the lipoprotein ( 1, 2 ), herein emphasis will be placed primarily on signaling events directly induced by apoA-I or HDL, which are likely occurring in response to cholesterol effl ux. To help leverage our present understanding of apoA-I-or HDL-initiated signaling in future studies, the signaling events and the proteins or mediators whose abundance or activity is altered by apoA-I or HDL in various cell types are summarized in Tables Abbreviations: AMPK, AMP-activated protein kinase; CaMKK, calcium/calmodulin-dependent protein kinase kinase; COX-2, cyclooxygenase type 2; DHCR24, 3 ␤ -hydroxysteriod-⌬ 24 reductase; eNOS, endothelial nitric-oxide synthase; EPC, endothelial progenitor cell; GKS3, glycogen synthase kinase 3; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; JAK2, Janus kinase 2; LKB1, liver kinase B1; MCP-1, monocyte chemoattractant protein-1; PKA, protein kinase A; PKC, protein kinase C; RCT, reverse cholesterol transport; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; SAA3, serum amyloid A3; SR-BI, scavenger receptor class B, type I; VCAM-1, vascular cell adhesion molecule-1; VSM, vascular smooth muscle.

HDL inhibits the effects of oxidized phospholipids on endothelial cell gene expression via multiple mechanisms

“…2 ). Signaling via SR-BI by HDL is primarily mediated by apoA1, and in this on NO production following SR-BI mediated eNOS activation ( 17,53 ). In contrast to these studies, we found that knockdown of SR-BI and cotreatment with blocking 6.…”

“…In addition to its role in cholesterol transport, HDL possesses anti-infl ammatory, antioxidant, and antithrombotic properties (17)(18)(19). These include directly inhibiting the oxidation of LDL, sequestering by-products of lipid oxidation, and promoting eNOS stability and accumulation in the vessel wall ( 17,18,(20)(21)(22).…”

“…In addition to its role in cholesterol transport, HDL possesses anti-infl ammatory, antioxidant, and antithrombotic properties (17)(18)(19). These include directly inhibiting the oxidation of LDL, sequestering by-products of lipid oxidation, and promoting eNOS stability and accumulation in the vessel wall ( 17,18,(20)(21)(22). In addition, members of our group have previously reported that HDL inhibits the induction by OxPAPC of chemotactic cytokines [interleukin (IL ) 8, monocyte chemotactic protein 1 (MCP-1) , and IL-6], UPR transcription factors [activating transcription factor 3 ( ATF3 ), activating transcription factor 4 ( ATF4 ), and X-box binding protein 1 ( XBP1 )], and sterol biosynthetic genes [LDL receptor (LDLR), Insig-1 , and HMG-CoA synthase] in HAECs ( 23 ).…”

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

“…rHDL preparations also were formulated to contain sphingosine-1-phosphate (rHDL + S1P) at a starting molar ratio of biological responses, including inhibition of lipid oxidation, impairment of leukocyte adhesion and monocyte activation, increased nitric oxide production, prostacyclin synthesis and flow-induced vasodilation, and the prevention of endothelial cell damage and death (5)(6)(7)(8). Studies have also shown that HDL can inhibit synthesis of matrix metalloproteinases, promote smooth muscle cell proliferation, and inhibit activation of platelets and the coagulation cascade (9).…”

Adenylyl cyclase 1 as a major isoform to generate cAMP signaling for apoA-1-mediated cholesterol efflux pathway

“…HDL apolipoprotein-mediated cholesterol removal pathway involves many cellular proteins, including cell surface binding proteins/receptors (3,4), intracellular signal transduction (3,5), vesicle transport (6,7) and exocytotic components (6,8).…”