Acute-phase High-density Lipoprotein Research Articles

Hydrolysis of polyhydroxy polyunsaturated fatty acid-glycerophosphocholines by Group IIA, V, and X secretory phospholipases A2.

It is widely accepted that unesterified polyunsaturated ω-6 and ω-3 fatty acids (PUFA) are converted through various lipoxygenases, cyclooxygenases, and cytochrome P450 enzymes to a range of oxygenated derivatives (oxylipins), among which the polyhydroxides of unesterified PUFA have recently been recognized as cell signaling molecules with anti-inflammatory and pro-resolving properties, known as specialized pro-resolving mediators (SPMs). This study investigates the mono-, di-, and trihydroxy 16:0/PUFA-GPCs, and the corresponding 16:0/SPM-GPC, in plasma lipoproteins. We describe the isolation and identification of mono-, di-, and trihydroxy AA, EPA, and DHA-GPC in plasma LDL, HDL, HDL3, and acute phase HDL using normal phase LC/ESI-MS, as previously reported. The lipoproteins contained variable amounts of the polyhydroxy-PUFA-GPC (0-10nmol/mg protein), likely the product of lipid peroxidation and the action of various lipoxygenases and cytochrome P450 enzymes on both free fatty acids and the parent GPCs. Polyhydroxy-PUFA-GPC was hydrolyzed to variable extent (20%-80%) by the different secretory phospholipases A2 (sPLA2 s), with Group IIA sPLA2 showing the lowest and Group X sPLA2 the highest activity. Surprisingly, the trihydroxy-16:0/PUFA-GPC of APHDL was largely absent, while large amounts of unidentified material had migrated in the free fatty acid elution area. The free fatty acid mass spectra were consistent with that anticipated for branched chain polyhydroxy fatty acids. There was general agreement between the masses determined by LC/ESI-MS for the polyhydroxy PUFA-GPC and the masses calculated for the GPC equivalents of resolvins, protectins, and maresins using the fatty acid structures reported in the literature.

Temporal Dynamics of High-Density Lipoprotein Proteome in Diet-Controlled Subjects with Type 2 Diabetes.

We examined the effect of mild hyperglycemia on high-density lipoprotein (HDL) metabolism and kinetics in diet-controlled subjects with type 2 diabetes (T2D). 2H2O-labeling coupled with mass spectrometry was applied to quantify HDL cholesterol turnover and HDL proteome dynamics in subjects with T2D (n = 9) and age- and BMI-matched healthy controls (n = 8). The activities of lecithin–cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), and the proinflammatory index of HDL were quantified. Plasma adiponectin levels were reduced in subjects with T2D, which was directly associated with suppressed ABCA1-dependent cholesterol efflux capacity of HDL. The fractional catabolic rates of HDL cholesterol, apolipoprotein A-II (ApoA-II), ApoJ, ApoA-IV, transthyretin, complement C3, and vitamin D-binding protein (all p < 0.05) were increased in subjects with T2D. Despite increased HDL flux of acute-phase HDL proteins, there was no change in the proinflammatory index of HDL. Although LCAT and CETP activities were not affected in subjects with T2D, LCAT was inversely associated with blood glucose and CETP was inversely associated with plasma adiponectin. The degradation rates of ApoA-II and ApoA-IV were correlated with hemoglobin A1c. In conclusion, there were in vivo impairments in HDL proteome dynamics and HDL metabolism in diet-controlled patients with T2D.

Abstract 380: SAA Lipidation and Delipidation by Hepatocytes

Serum amyloid A (SAA) is one of the most striking acute phase reactants that can rapidly increase 1000-fold in plasma concentration in response to inflammatory cytokines. SAA in lipid-free form exhibits pro-inflammatory activities, but its putative physiological function(s) are poorly understood. SAA is produced and secreted largely by the liver and is present in plasma mainly as an HDL apolipoprotein. The pathways by which SAA is lipidated and incorporated into HDL are poorly understood. Plasma SAA is cleared more rapidly than the other major HDL apolipoproteins, but pathways involved in its delipidation and plasma clearance have also not been defined. In this study we examined how SAA is lipidated in primary hepatocytes and how such lipidation relates to the formation of nascent HDL particles. Endogenous hepatocyte SAA was lipidated and released from cells as large particles that were distinct from apoA-I-containing nascent HDL’s. Unlike apoA-I, formation of these SAA-containing particles was independent of ABCA-I. Similarly, when SAA was exogenously added to cells, SAA was lipidated to form nascent particles that were distinct from apoA-I-containing particles. We further studied the interaction of lipid-free and HDL-bound SAA with hepatocytes. Both in lipid-free form and as part of HDL, SAA exhibited significantly greater binding to cells than apoA-I or apoA-II. Binding studies were also carried out with normal and acute phase HDL’s isolated from control and SAA-deficient mice. Together, the results suggested that SAA, unlike apoA-I, is selectively removed from HDL by binding to hepatocytes. These findings may provide new insights into SAA metabolism and function.

Serum amyloid A and atherosclerosis.

Atherosclerosis is a chronic inflammation associated with increased expression of the acute phase isoforms of serum amyloid A (SAA) and in humans is a plasma biomarker for future cardiovascular events. However, whether SAA is only a biomarker or participates in the development of cardiovascular disease is not well characterized. The purpose of this review is to summarize putative functions of SAA relevant to atherogenesis and in-vivo murine studies that directly examine the effect of SAA on atherosclerosis. Modulation of the expression of SAA1 and/or SAA2 in murine models of atherosclerosis suggests that SAA promotes early atherogenesis. SAA secreted from bone-marrow-derived cells contributes to this antiatherogenic phenotype. SAA also promotes angiotensin-induced abdominal aneurysm in atherogenic mouse models. The reduction in atherosclerosis may be due, at least in part, to remodeling of the acute phase HDL to reduce its capacity to promote cholesterol efflux and reduce its anti-inflammatory ability. SAA is more than a marker of cardiovascular disease and is a participant in the early atherogenic process.

Abstract 388: Impact of Individual Acute Phase Serum Amyloid A Isoforms on HDL Metabolism in Mice

The acute phase reactant serum amyloid A (SAA) is an HDL apolipoprotein that exhibits biological activities as a pro-inflammatory mediator, but its physiological function(s) are poorly understood. Possible functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are also unclear. Mice deficient in either SAA1.1 or SAA2.1 were used to investigate SAA isoform plasma clearance rates and effects on HDL structure, composition and apolipoprotein catabolism. The absence of either isoform did not affect the size of the normally enlarged HDL found in acute phase wild type mice, and did not result in significant changes in HDL lipid composition. Plasma clearance rates of normal and acute phase HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCR’s) of apoA-I, apoA-II and SAA were distinct, indicating that neither normal nor acute phase particles are cleared as intact particles. No significant difference was found between the FCR’s of SAA1.1 and SAA2.1 in acute phase mice, suggesting that the selective deposition of SAA1.1 observed in amyloid plaques is not associated with a difference in the rates of plasma clearance of the isoforms. In the absence of the HDL receptor SR-BI, the clearance rate of SAA was reduced by about 30% and remained significantly greater compared to that of apoA-I and apoA-II, indicating a relatively minor role of SR-BI in SAA clearance. These studies contribute to our understanding of the metabolism of SAA and its effects on acute phase HDL composition and catabolism.

Thermal transitions in serum amyloid A in solution and on the lipid: implications for structure and stability of acute-phase HDL

Serum amyloid A (SAA) is an acute-phase protein that circulates mainly on plasma HDL. SAA interactions with its functional ligands and its pathogenic deposition in reactive amyloidosis depend, in part, on the structural disorder of this protein and its propensity to oligomerize. In vivo, SAA can displace a substantial fraction of the major HDL protein, apoA-I, and thereby influence the structural remodeling and functions of acute-phase HDL in ways that are incompletely understood. We use murine SAA1.1 to report the first structural stability study of human plasma HDL that has been enriched with SAA. Calorimetric and spectroscopic analyses of these and other SAA-lipid systems reveal two surprising findings. First, progressive displacement of the exchangeable fraction of apoA-I by SAA has little effect on the structural stability of HDL and its fusion and release of core lipids. Consequently, the major determinant for HDL stability is the nonexchangeable apoA-I. A structural model explaining this observation is proposed, which is consistent with functional studies in acute-phase HDL. Second, we report an α-helix folding/unfolding transition in SAA in the presence of lipid at near-physiological temperatures. This new transition may have potentially important implications for normal functions of SAA and its pathogenic misfolding.

Characterization of reconstituted high-density lipoprotein particles formed by lipid interactions with human serum amyloid A

The acute-phase human protein serum amyloid A (SAA) is enriched in high-density lipoprotein (HDL) in patients with inflammatory diseases. Compared with normal HDL containing apolipoprotein A-I, which is the principal protein component, characteristics of acute-phase HDL containing SAA remain largely undefined. In the present study, we examined the physicochemical properties of reconstituted HDL (rHDL) particles formed by lipid interactions with SAA. Fluorescence and circular dichroism measurements revealed that although SAA was unstructured at physiological temperature, α-helix formation was induced upon binding to phospholipid vesicles. SAA also formed rHDL particles by solubilizing phospholipid vesicles through mechanisms that are common to other exchangeable apolipoproteins. Dynamic light scattering and nondenaturing gradient gel electrophoresis analyses of rHDL after gel filtration revealed particle sizes of approximately 10nm, and a discoidal shape was verified by transmission electron microscopy. Thermal denaturation experiments indicated that SAA molecules in rHDL retained α-helical conformations at 37°C, but were almost completely denatured around 60°C. Furthermore, trypsin digestion experiments showed that lipid binding rendered SAA molecules resistant to protein degradation. In humans, three major SAA1 isoforms (SAA1.1, 1.3, and 1.5) are known. Although these isoforms have different amino acids at residues 52 and 57, no major differences in physicochemical properties between rHDL particles resulting from lipid interactions with SAA isoforms have been found. The present data provide useful insights into the effects of SAA enrichment on the physicochemical properties of HDL.

SP0145 HDL as a Pro-Inflammatory Agent

Although HDL levels are traditionally inversely related to atherosclerosis, the relationship is complex and involves both HDL quantity and function. HDL has been described as “chameleon-like,” anti-inflammatory in the basal...

Heparan Sulfate Dissociates Serum Amyloid A (SAA) from Acute-phase High-density Lipoprotein, Promoting SAA Aggregation

Inflammation-related (AA) amyloidosis is a severe clinical disorder characterized by the systemic deposition of the acute-phase reactant serum amyloid A (SAA). SAA is normally associated with the high-density lipoprotein (HDL) fraction in plasma, but under yet unclear circumstances, the apolipoprotein is converted into amyloid fibrils. AA amyloid and heparan sulfate (HS) display an intimate relationship in situ, suggesting a role for HS in the pathogenic process. This study reports that HS dissociates SAA from HDLs isolated from inflamed mouse plasma. Application of surface plasmon resonance spectroscopy and molecular modeling suggests that HS simultaneously binds to two apolipoproteins of HDL, SAA and ApoA-I, and thereby induce SAA dissociation. The activity requires a minimum chain length of 12-14 sugar units, proposing an explanation to previous findings that short HS fragments preclude AA amyloidosis. The results address the initial events in the pathogenesis of AA amyloidosis.

Psoriasis: it's more than just the skin

Journal of Lipid Research Volume 53, 2012 1427 Psoriasis is a skin disease that is accompanied by systemic infl ammation and is one of the most common infl ammatory disorders, estimated to effect between 1 and 3% of the population ( 1 ). It is characterized by epidermal hyperproliferation and dermal infl ammation. The etiology of psoriasis is unknown but genetic factors play a role. Psoriasis may begin at any age but has two peak periods of onset: between 15 and 25 and between 50 to 60 years of age. In many patients, psoriasis affects only a small area of the skin (<2% of body surface area) whereas in other patients, the disease can be quite severe, affecting a large portion of the skin. The cutaneous manifestations lead to considerable morbidity and the emotional burden of severe psoriasis has been shown to be similar to that seen in patients with cancer, diabetes, and heart disease. However, it is important to recognize that psoriasis is associated with systemic metabolic disorders including an increased prevalence of the metabolic syndrome, obesity, diabetes, dyslipidemia, and cardiovascular disease (CVD) ( 2 ‐ 4 ). The increased risk of CVD in patients with psoriasis was fi rst reported by McDonald and Calabresi in 1978 ( 5 ). They observed that patients with psoriasis had a 2.2-fold increase in CVD compared with controls. Since then, a large number of additional epidemiological studies have also shown that the risk of CVD is increased in patients with psoriasis [see Tobin et al. ( 4 ) for an excellent review of the literature] ( 2 ‐ 5 ). Of note psoriasis still conferred an increased risk even when the studies controlled for the usual CVD risk factors such as age, sex, diabetes, hypertension, hyperlipidemia, smoking, and obesity, implying that psoriasis causes abnormalities that increase the risk of CVD that are not dependent on the usual risk factors ( 2 ‐ 4 ). Moreover, studies have suggested that the more severe the psoriasis the greater the risk of CVD. Further, supporting the link of psoriasis with atherosclerosis are studies showing that patients with psoriasis have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound ( 6 ‐ 8 ). A very large number of studies have compared serum lipid levels in patients with psoriasis to control subjects ( 2 ‐ 4 ). Most of these reports included only a small number

ATP binding cassette G1-dependent cholesterol efflux during inflammation

ATP binding cassette transporter G1 (ABCG1) mediates the transport of cellular cholesterol to HDL, and it plays a key role in maintaining macrophage cholesterol homeostasis. During inflammation, HDL undergoes substantial remodeling, acquiring lipid changes and serum amyloid A (SAA) as a major apolipoprotein. In the current study, we investigated whether remodeling of HDL that occurs during acute inflammation impacts ABCG1-dependent efflux. Our data indicate that lipid free SAA acts similarly to apolipoprotein A-I (apoA-I) in mediating sequential efflux from ABCA1 and ABCG1. Compared with normal mouse HDL, acute phase (AP) mouse HDL containing SAA exhibited a modest but significant 17% increase in ABCG1-dependent efflux. Interestingly, AP HDL isolated from mice lacking SAA (SAAKO mice) was even more effective in promoting ABCG1 efflux. Hydrolysis with Group IIA secretory phospholipase A(2) (sPLA(2)-IIA) significantly reduced the ability of AP HDL from SAAKO mice to serve as a substrate for ABCG1-mediated cholesterol transfer, indicating that phospholipid (PL) enrichment, and not the presence of SAA, is responsible for alterations in efflux. AP human HDL, which is not PL-enriched, was somewhat less effective in mediating ABCG1-dependent efflux compared with normal human HDL. Our data indicate that inflammatory remodeling of HDL impacts ABCG1-dependent efflux independent of SAA.

Impact of serum amyloid A on high density lipoprotein composition and levels

Serum amyloid A (SAA) is an acute-phase protein mainly associated with HDL. To study the role of SAA in mediating changes in HDL composition and metabolism during inflammation, we generated mice in which the two major acute-phase SAA isoforms, SAA1.1 and SAA2.1, were deleted [SAA knockout (SAAKO) mice], and induced an acute phase to compare lipid and apolipoprotein parameters between wild-type (WT) and SAAKO mice. Our data indicate that SAA does not affect apolipoprotein A-I (apoA-I) levels or clearance under steady-state conditions. HDL and plasma triglyceride levels following lipopolysaccharide administration, as well as the decline in liver expression of apoA-I and apoA-II, did not differ between both groups of mice. The expected size increase of WT acute-phase HDL was surprisingly also seen in SAAKO acute-phase HDL despite the absence of SAA. HDLs from both mice showed increased phospholipid and unesterified cholesterol content during the acute phase. We therefore conclude that in the mouse, SAA does not impact HDL levels, apoA-I clearance, or HDL size during the acute phase and that the increased size of acute-phase HDL in mice is associated with an increased content of surface lipids, particularly phospholipids, and not surface proteins. These data need to be transferred to humans with caution due to differences in apoA-I structure and remodeling functions.

High-density lipoprotein and the acute phase response

Inflammation and the concomitant acute phase response induce marked changes in the lipoprotein profile, particularly the high-density lipoprotein (HDL) fraction. The present review describes the transfer proteins and lipases that remodel HDL and regulate its plasma levels, discusses the changes occurring in their activities during inflammation, and the influence of this altered remodeling on HDL function. The review will also discuss the contribution of the ATP-binding-membrane-cassette transporters to the protective actions of HDL. Studies using different models showed that remodeling of acute phase HDL in vitro generates pre-beta migrating particles capable of cholesterol efflux. Induction of the acute phase response in humans resulted in a reduction of HDL phospholipids without a change in HDL-cholesterol. However, the capacity of HDL to promote cholesterol efflux ex vivo was impaired. Studies with ATP-binding-membrane-cassette transporter A1 and ATP-binding-membrane-cassette transporter G1 knockout mice demonstrated anti-inflammatory roles for these transporters by virtue of reducing cell-membrane-free cholesterol and lipid raft content, thus attenuating proinflammatory signaling pathways. It is well known that HDL has anti-inflammatory properties that are diminished during inflammation. Acute phase HDL contains serum amyloid A that can be liberated during remodeling by cholesteryl ester transfer protein and secretory phospholipase A2, or other inflammatory factors. The ability of serum amyloid A and apolipoprotein A-I to promote cholesterol efflux may confer protective effects during the acute phase response.

SR-BI Selective Lipid Uptake

The purpose of this study was to investigate the interaction of SAA and SR-BI in remodeling of acute phase HDL (AP HDL). We used SAA and SR-BI adenoviral vector expression models to study the interaction between these entities. SR-BI processing of mouse AP HDL generated progressively smaller discreet HDL particles with distinct apolipoprotein compositions. SR-BI actions segregated apolipoproteins with the smallest particles containing only apoA-I. Larger remnants contained apoA-I, apoA-II, and SAA. Small apoA-I only particles failed to associate with preformed HDL, whereas larger remnants readily did. The presence of SAA on SR-BI-processed HDL particles propelled apoA-I to a small lipid-poor form and accelerated apoA-I catabolism. Data indicate that after core and surface HDL lipid perturbation by SR-BI, SAA propels apoA-I to a small lipid-poor form while accelerating HDL metabolism.

Inflammation Impairs Reverse Cholesterol Transport In Vivo

Inflammation is proposed to impair reverse cholesterol transport (RCT), a major atheroprotective function of high-density lipoprotein (HDL). The present study presents the first integrated functional evidence that inflammation retards numerous components of RCT. We used subacute endotoxemia in the rodent macrophage-to-feces RCT model to assess the effects of inflammation on RCT in vivo and performed proof of concept experimental endotoxemia studies in humans. Endotoxemia (3 mg/kg SC) reduced (3)H-cholesterol movement from macrophage to plasma and (3)H-cholesterol associated with HDL fractions. At 48 hours, bile and fecal counts were markedly reduced consistent with downregulation of hepatic expression of ABCG5, ABCG8, and ABCB11 biliary transporters. Low-dose lipopolysaccharide (0.3 mg/kg SC) also reduced bile and fecal counts, as well as expression of biliary transporters, but in the absence of effects on plasma or liver counts. In vitro, lipopolysaccharide impaired (3)H-cholesterol efflux from human macrophages to apolipoprotein A-I and serum coincident with reduced expression of the cholesterol transporter ABCA1. During human (3 ng/kg; n=20) and murine endotoxemia (3 mg/kg SC), ex vivo macrophage cholesterol efflux to acute phase HDL was attenuated. We provide the first in vivo evidence that inflammation impairs RCT at multiple steps in the RCT pathway, particularly cholesterol flux through liver to bile and feces. Attenuation of RCT and HDL efflux function, independent of HDL cholesterol levels, may contribute to atherosclerosis in chronic inflammatory states including obesity, metabolic syndrome, and type 2 diabetes.

AA amyloidosis associated with a mutated serum amyloid A4 protein

AA amyloidosis invariably has been associated with fibrillar deposits of the acute phase high-density lipoprotein serum amyloid A isotypes SAA1 and SAA2. We now report the first case in a patient with no antecedent history of a chronic inflammatory or neoplastic process whose pathologic renal deposits were comprised of a mutated form of the constitutively expressed serum amyloid A4 (SAA4) protein. Analyses by tandem mass spectrometry of amyloid extracted from kidney biopsies revealed a component identical in sequence to the N-terminal portion of SAA4, except for the substitution of glycine for tryptophan at position 22 (W22G). Sequencing of genomic DNA using SAA4-specific primers showed a TGG to GGG transversion in codon 22 that accounted for the observed modification. Confirmation of the SAA4 nature of the amyloid was obtained immunohistochemically. Notably, only wild-type SAA4 was detected by mass spectrometry in the patient's serum and its concentration was within normal limits. Given the substitution of an amino acid lacking a side chain for a bulky residue, we posit that the W22G alteration would profoundly affect SAA4 stability, rendering it amyloidogenic. Our studies provide the first evidence for a novel type of AA amyloidosis in which the fibrils were formed from a mutated SAA4 protein.

Acute-Phase-HDL Remodeling by Heparan Sulfate Generates a Novel Lipoprotein with Exceptional Cholesterol Efflux Activity from Macrophages

During episodes of acute-inflammation high-density lipoproteins (HDL), the carrier of so-called good cholesterol, experiences a major change in apolipoprotein composition and becomes acute-phase HDL (AP-HDL). This altered, but physiologically important, HDL has an increased binding affinity for macrophages that is dependent on cell surface heparan sulfate (HS). While exploring the properties of AP-HDL∶HS interactions we discovered that HS caused significant remodeling of AP-HDL. The physical nature of this change in structure and its potential importance for cholesterol efflux from cholesterol-loaded macrophages was therefore investigated. In the presence of heparin, or HS, AP-HDL solutions at pH 5.2 became turbid within minutes. Analysis by centrifugation and gel electrophoresis indicated that AP-HDL was remodeled generating novel lipid poor particles composed only of apolipoprotein AI, which we designate β2. This remodeling is dependent on pH, glycosaminoglycan type, is promoted by Ca2+ and is independent of protease or lipase activity. Compared to HDL and AP-HDL, remodeled AP-HDL (S-HDL-SAA), containing β2 particles, demonstrated a 3-fold greater cholesterol efflux activity from cholesterol-loaded macrophage. Because the identified conditions causing this change in AP-HDL structure and function can exist physiologically at the surface of the macrophage, or in its endosomes, we postulate that AP-HDL contains latent functionalities that become apparent and active when it associates with macrophage cell surface/endosomal HS. In this way initial steps in the reverse cholesterol transport pathway are focused at sites of injury to mobilize cholesterol from macrophages that are actively participating in the phagocytosis of damaged membranes rich in cholesterol. The mechanism may also be of relevance to aspects of atherogenesis.

HDL cholesterol transport during inflammation

The aim of this article is to review recent advances made towards understanding how inflammation and acute phase proteins, particularly serum amyloid A and group IIa secretory phospholipase A2, may alter reverse cholesterol transport by HDL during inflammation and the acute phase response. Findings suggest that the decreased apoA-I content and markedly increased serum amyloid A content in HDL during the acute phase response result from reciprocal and coordinate transcriptional regulation of these proteins as well as HDL remodeling by group IIa secretory phospholipase A2. Serum amyloid A functions efficiently in a lipid-free or lipid-poor form to promote cholesterol efflux by ATP binding cassette protein ABCA1, evidently by functioning directly as an acceptor for cholesterol efflux as well as by increasing the availability of cellular free cholesterol. Serum amyloid A increases the ability of acute phase HDL to serve as an acceptor for SR-BI-dependent cellular cholesterol efflux. Altered remodeling of HDL by group IIa secretory phospholipase A2 in concert with cholesterol ester transfer protein may contribute to the generation of lipid-poor apoA-I and serum amyloid A acceptors for cholesterol efflux. Current data support a model for the acute phase response in which serum amyloid A and sPLA2-IIa, present at sites of inflammation and tissue damage, play a protective role by enhancing cellular cholesterol efflux, thereby promoting the removal of excess cholesterol from macrophages.

Regulation of SR-BI-mediated selective lipid uptake in Chinese hamster ovary-derived cells by protein kinase signaling pathways

Scavenger receptor, class B, type I (SR-BI) mediates binding and internalization of a variety of lipoprotein and nonlipoprotein ligands, including HDL. Studies in genetically engineered mice revealed that SR-BI plays an important role in HDL reverse cholesterol transport and protection against atherosclerosis. Understanding how SR-BI's function is regulated may reveal new approaches to therapeutic intervention in atherosclerosis and heart disease. We utilized a model cell system to explore pathways involved in SR-BI-mediated lipid uptake from and signaling in response to distinct lipoprotein ligands: the physiological ligand, HDL, and a model ligand, acetyl LDL (AcLDL). In Chinese hamster ovary-derived cells, murine SR-BI (mSR-BI) mediates lipid uptake via distinct pathways that are dependent on the lipoprotein ligand. Furthermore, HDL and AcLDL activate distinct signaling pathways. Finally, mSR-BI-mediated selective lipid uptake versus endocytic uptake are differentially regulated by protein kinase signaling pathways. The protein kinase C (PKC) activator PMA and the phosphatidyl inositol 3-kinase inhibitor wortmannin increase the degree of mSR-BI-mediated selective lipid uptake, whereas a PKC inhibitor has the opposite effect. These data demonstrate that SR-BI's selective lipid uptake activity can be acutely regulated by intracellular signaling cascades, some of which can originate from HDL binding to murine SR-BI itself.

Understanding Changes in High Density Lipoproteins During the Acute Phase Response

During infection and inflammation there is a cascade of reactions that occurs in the host collectively known as the acute-phase response (APR).1 Besides alterations in acute-phase reactants (plasma proteins), the APR is also associated with changes in lipoproteins.2 Increasing evidence suggests that high density lipoproteins (HDL) are a critical part of the acute phase response (APR) of the innate immune system.3 During infection and inflammation, there is a reduction in levels of several plasma proteins involved in HDL-mediated reverse cholesterol transport and inhibiting plasma lipid oxidation, such as lecithin:cholesterol acyltransferase (LCAT), cholesterol ester transfer protein, phospholipid transfer protein, hepatic lipase, apolipoprotein A-I (apoA-I), and paraoxonase (PON).2 Moreover, the composition of circulating HDL during an APR, also known as acute-phase HDL, is altered. Analysis of the lipid composition shows that acute-phase HDL is depleted in cholesterol ester but enriched in free cholesterol, triglyceride, and free tty acids.4 Changes in the phospholipid content of acute-phase HDL was shown to be more variable, having increased in one study5 but decreased in another.6 The levels of apolipoprotein J (apoJ or clusterin) and serum amyloid A (SAA) increase several fold in …