Many enzymes of sphingolipid metabolism are regulated in response to extra- and intracellular stimuli and in turn serve as regulators of levels of bioactive lipids (such as sphingosine, ceramide, sphingosine 1-phosphate, and diacylglycerol), and as such, they serve a prototypical modular function in cell regulation. However, lipid metabolism is also closely interconnected in that a product of one enzyme serves as a substrate for another. Moreover, many cell stimuli regulate more than one of these enzymes, thus adding to the complexity of regulation of lipid metabolism. In this paper, we review the status of enzymes of sphingolipid metabolism in cell regulation and propose a role for these enzymes in integration of cell responses, a role that builds on the modular organization while also taking advantage of the complexity and interconnectedness of lipid metabolism, thus providing for a combinatorial mechanism of generating diversity in cell responses. This may be a general prototype for the involvement of metabolic pathways in cell regulation.
The very low density lipoprotein (VLDL) receptor binds apolipoprotein E-rich lipoproteins as well as the 39-kDa receptor-associated protein (RAP). Ligand blotting experiments using RAP and immunoblotting experiments using an anti-VLDL receptor IgG detected the VLDL receptor in detergent extracts of human aortic endothelial cells, human umbilical vein endothelial cells, and human aortic smooth muscle cells. To gain insight into the role of the VLDL receptor in the vascular endothelium, its ligand binding properties were further characterized. In vitro binding experiments documented that lipoprotein lipase (LpL), a key enzyme in lipoprotein catabolism, binds with high affinity to purified VLDL receptor. In addition, urokinase complexed with plasminogen activator-inhibitor type I (uPA⅐PAI-1) also bound to the purified VLDL receptor with high affinity. To assess the capacity of the VLDL receptor to mediate the cellular internalization of ligands, an adenoviral vector was used to introduce the VLDL receptor gene into a murine embryonic fibroblast cell line deficient in the VLDL receptor and the LDL receptorrelated protein, another endocytic receptor known to bind LpL and uPA⅐PAI-1 complexes. Infected fibroblasts that express the VLDL receptor mediate the cellular internalization of 125 I-labeled LpL and uPA⅐PAI-1 complexes, leading to their degradation. Non-infected fibroblasts or fibroblasts infected with the lacZ gene did not internalize these ligands. These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA⅐PAI-1 complexes. Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor. The low density lipoprotein (LDL)1 receptor gene family includes the LDL receptor (1), the very low density lipoprotein (VLDL) receptor (2), the LDL receptor-related protein (LRP) (3), and glycoprotein 330 (4). Together, these molecules have important roles in the catabolism of lipoproteins, proteinases, proteinase-inhibitor complexes, and matrix proteins (for reviews, see Refs. 5-8). The members of this receptor family share structural motifs including cysteine-rich epidermal growth factor-like repeats, cysteine-rich ligand binding repeats, repeats containing the tetrapeptide sequence tyrosinetryptophan-threonine-aspartic acid, and an asparagine-proline-X-tyrosine sequence within the cytoplasmic tail, which is responsible for endocytic signaling in coated pits.The most recently identified member of this receptor family is the VLDL receptor (2), so named because it appeared to specifically bind VLDL, probably via interaction with apolipoprotein E (apo E). At present, however, the physiological role of the VLDL receptor is uncertain. This receptor is most abundant in skeletal muscle, heart, adipose tissue, and brain (9 -11), tissues which metabolize fatty acids as an energy source. This fact, and the observation that the V...
Lp(a) is a major inherited risk factor associated with premature heart disease and stroke. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to influence plasminogen activation as well as its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that fibroblasts expressing the human VLDL receptor can mediate endocytosis of Lp(a), leading to its degradation within lysosomes.
High density lipoproteins (HDL) are major plasma carriers of sphingosine 1-phosphate (S1P). Here we show that HDL increases endothelial barrier integrity as measured by electric cell substrate impedance sensing. S1P was implicated as the mediator in this process through findings showing that pertussis toxin, an inhibitor of G i -coupled S1P receptors, as well as antagonists of the S1P receptor, S1P1, inhibited barrier enhancement by HDL. Additional findings show that HDL stimulates endothelial cell activation of Erk1/2 and Akt, signaling pathway intermediates that have been implicated in S1P-dependent endothelial barrier activity. HDL was also found to promote endothelial cell motility, a process that may also relate to endothelial barrier function in the context of a vascular injury response. The effects of HDL on endothelial cell Erk1/2 and Akt activation and motility were suppressed by pertussis toxin and S1P1 antagonists. However, both HDL-induced barrier enhancement and HDL-induced motility showed a greater dependence on Akt activation as compared with Erk1/2 activation. Together, the findings indicate that HDL has endothelial barrier promoting activities, which are attributable to its S1P component and signaling through the S1P1/Akt pathway.Sphingosine 1-phosphate (S1P) 2 is a plasma-borne lysosphingolipid that has been shown to regulate endothelial barrier integrity (1). For example, treatment of cultured endothelial cells with S1P associated with the carrier albumin acts to increase endothelial barrier activity as indicated by increased transendothelial electrical resistance (2, 3). Moreover, S1P administration greatly reduces lung capillary leakage induced in mice by lipopolysaccharide treatment (4). Mechanistically, S1P acts to enhance tight junction formation in neighboring endothelial cells by influencing subcellular distributions of tight junction components including ZO-1 and claudin-5 (5). In addition, S1P induces endothelial cortical actin assembly (1) and relocation of endothelial cell junctional adhesion molecules including platelet endothelial cell adhesion molecule and vascular endothelial-cadherin to cell-cell junctional areas (5).In plasma, S1P is found associated with multiple lipoproteins including low density lipoproteins, very low density lipoproteins, and high density lipoproteins (HDL). However, the bulk of the lipoprotein particle-associated S1P (54%) is bound to HDL (6). A number of recent studies point to the S1P cargo of HDL as being a mediator of many of the cardiovascular effects of HDL including the ability to promote vasodilation, vasoconstriction, and angiogenesis, protect against ischemia/reperfusion injury, and inhibit/reverse atherosclerosis (7). One important cardiovascular-related effect of S1P that has not yet been attributed to HDL is regulation of endothelial barrier activity, a major physiological function of the endothelium. Here we investigate the role of HDL as a regulator of endothelial barrier integrity processes known to be dependent on S1P signaling. EXPERIMEN...
The lysosphingolipid sphingosine 1-phosphate (S1P) is a component of HDL. Findings from a growing number of studies indicate that S1P is a mediator of many of the cardiovascular effects of HDL, including the ability to promote vasodilation, vasoconstriction, and angiogenesis, protect against ischemia/reperfusion injury, and inhibit/ reverse atherosclerosis. These latter cardioprotective effects are being shown to involve the S1P-mediated suppression of inflammatory processes, including reduction of the endothelial expression of monocyte and lymphocyte adhesion molecules, decreased recruitment of polymorphonuclear cells to sites of infarction, and blocking of cardiomyocyte apoptosis after myocardial infarction. This review article summarizes the evidence that S1P as a component of HDL serves to regulate vascular cell and lymphocyte behaviors associated with cardiovascular (patho)physiology. (1) were the first to show that the lysosphingolipid sphingosine 1-phosphate (S1P) was a component of human plasma, present at a concentration of ?200 nM. After these findings were published, Sachinidis et al. (2) reported that human LDL and HDL possess a signaling activity that promoted extracellular signal-regulated protein kinase phosphorylation in a pertussis toxin-sensitive manner. HPLC fractionation of plasma LDL and HDL showed that the lipoproteinassociated signaling activity had a chromatographic elution profile corresponding to that of purified S1P. Further evidence appeared demonstrating that ?65% of the S1P in blood is associated with the lipoproteins LDL, VLDL, and HDL, with the bulk of lipoprotein-associated S1P (?54%) bound to HDL (3). Measurements of the S1P content of human HDL and LDL particles show that these lipoproteins contain ?180 and 70 pmol S1P/mg protein, respectively (4). Together, these findings have set the stage for investigations into the mechanism of S1P incorporation into lipoproteins and the physiological significance of lipoproteins as carriers of S1P, and the findings of these investigations are summarized in this review.
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