Published online before print June 12, 2008, doi: 10.1161/CIRCRESAHA.108.178756
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© 2008 American Heart Association, Inc.
Molecular Medicine |
Enhanced Cellular Uptake of Remnant High-Density Lipoprotein Particles
A Mechanism for High-Density Lipoprotein Lowering in Insulin Resistance and Hypertriglyceridemia
From the Departments of Medicine and Physiology (C.X., T.W., L.S., G.F.L.) and Department of Laboratory Medicine and Pathobiology (P.W.C.), University of Toronto, Ontario, Canada; Departments of Biochemistry and Biomedical Sciences (Y.Z., B.T.), McMaster University, Hamilton, Ontario, Canada; and Department of Medicine (S.M., T.V., J.W.H.), University of Washington School of Medicine, Seattle.
Correspondence to Dr. Gary F. Lewis, MD FRCPC, Room EN12-218, The Toronto General Hospital, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada. E-mail gary.lewis{at}uhn.on.ca
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Abstract |
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A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. The increased binding of remnant HDL was not mediated by the low-density lipoprotein receptor or scavenger receptor class B type I (SR-BI), because enhanced remnant HDL binding was observed in low-density lipoprotein receptor–deficient cells with or without SR-BI overexpression. Disruption of cell surface heparan sulfate proteoglycans or blockage of apolipoprotein E–mediated lipoprotein binding also did not abolish the enhanced remnant HDL binding. Our observations indicate that remodeling of triglyceride-enriched HDL by hepatic lipase may result in enhanced binding, internalization, and degradation in tissues involved in HDL catabolism, contributing to rapid clearance and overall lowering of plasma HDL cholesterol in insulin resistance and hypertriglyceridemia.
Key Words: HDL • hepatic lipase • insulin resistance • hypertriglyceridemia
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Introduction |
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Population studies have shown a highly reproducible, inverse correlation between plasma concentrations of high-density lipoprotein cholesterol (HDL-c), apolipoprotein (apo)A-I and the risk of atherosclerotic cardiovascular diseases.1,2 A thorough understanding of the cellular/molecular mechanisms regulating HDL metabolism is important to the development of new therapeutic approaches to prevent cardiovascular diseases.3
Low HDL is a characteristic feature of insulin resistance and hypertriglyceridemia,4 which is mainly attributable to enhanced clearance but not decreased production of HDL particles.5 The precise mechanisms underlying enhanced HDL catabolism are not clear. Intravascular remodeling of HDL by lipid transfer factors, lipases, and non-HDL lipoproteins plays a critical role in HDL metabolism.6 In insulin resistance and hypertriglyceridemia, HDL particles are enriched with triglycerides (TGs) by enhanced lipid exchange with the increased number and size of TG-rich lipoproteins, a process mediated by cholesteryl ester transfer protein.7 Increased hepatic lipase (HL) activity accompanies TG enrichment of HDL particles in these states.8 HL hydrolysis of TG-rich HDL induces the formation of pre–β1-HDL, leaving a residual 
-migrating HDL particle referred to as remnant HDL.9,10 Remnant HDL particles have compositional and conformational features that are distinct from TG-rich HDL, and many of these features may affect their affinity and binding to cell surface binding sites.11,12 Shedding and rapid renal filtration and degradation of lipid-poor or lipid-free apoA-I that results from the HDL lipolysis may contribute to low HDL-c. We have previously demonstrated that TG enrichment in combination with HL lipolysis of HDL enhances HDL catabolism in vivo.13–16 The liver, kidney, and steroidogenic tissues are major sites of HDL catabolism.17,18 The liver has been recognized as the major site for selective HDL lipid uptake mainly mediated through scavenger receptor class B type I (SR-BI) in the process of reverse cholesterol transport.19,20 The kidney is the principal tissue for the uptake of apoA-I,21,22 possibly through filtration at the glomerulus and catabolism by the renal tubular cells via the cubilin/megalin receptor complex.23,24 For these reasons, we chose to study the binding of HDL to human liver and kidney cell lines in the present study.
Clearance of HDL may be through receptor-mediated or nonreceptor-mediated pathways. Cholesteryl ester may be transferred to circulating apoB-containing lipoproteins and then delivered to the liver25 or may be selectively removed from the particle by the liver or extrahepatic tissues without catabolism of the whole particle.19 Alternatively, HDL may be removed by endocytic uptake and degradation of the whole particle, a process referred to as holoparticle uptake.6 Holoparticle HDL and apoA-I uptake and degradation are known to occur in both liver and kidney.17,21 A number of receptors have been identified that participate in either selective cholesteryl ester uptake or holoparticle uptake by tissues.26 SR-BI exhibits high-affinity binding to HDL and plays a major role in HDL selective lipid uptake.19,20 Other plasma membrane proteins such as cubilin,27 LDL receptor–related protein,28 HDL-binding proteins 1 and 2,29 HDL binding protein,30 apoA-I binding protein,31 and ectopic β-chain of ATP synthase32 have also been proposed as physiologically relevant HDL receptors, although their roles in HDL catabolism in vivo have not been fully elucidated.
We hypothesized that the more rapid HDL clearance from the circulation in insulin resistance and hypertriglyceridemia is associated with enhanced cellular uptake of HDL particles that are modified by TG enrichment and increased HL lipolysis. We prepared 3 species of HDL, ie, unmodified HDL, HDL enriched with TG from very-low-density lipoprotein (VLDL) ex vivo and TG-enriched HDL hydrolyzed by HL, and we examined their binding, internalization, and degradation in human liver and kidney cell lines. We further examined the potential roles of several factors in mediating their binding properties. We elected to use whole HDL, rather than 1 specific HDL subfraction (such as HDL2), firstly to exactly mimic the conditions of our previous in vivo studies13,14 to relate the present in vitro findings to our previous in vivo observations and, secondly, to more closely mimic the real life situation in humans, in whom the HDL lipoprotein fraction is heterogeneous with respect to size, density, and composition.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
Cells
HepG2 (human hepatoma) and HEK293 (human embryonic kidney) cells were from the American Tissue Culture Collection and cultured in -minimal essential medium and DMEM, respectively, both supplemented with 10% FBS. CHO cells and ldlA7 cells were maintained in Ham’s/F12 supplemented with 5% FBS and 2 mmol/L L-glutamine. ldlA7 cells with stable transfection of human SR-BI (ldlA[hSR-BI]) were selected and maintained in medium containing 400 µg/mL Geneticin (Invitrogen, Burlington, Ontario, Canada). One day before binding assays, CHO, ldlA7, and ldlA[hSR-BI] cells were washed and refed with medium containing 3% newborn calf lipoprotein-deficient serum.
Preparation and Analysis of HDL
Human fasting plasma was incubated with VLDL (final TG 
5 mmol/L) at 37°C for 6 hours to enrich HDL with TG.13,14 HDL (d=1.063 to 1.25) was isolated by sequential ultracentrifugation and dialyzed.13 HDL from fasting plasma and from the plasma after TG enrichment are referred to as native and TG-rich HDL, respectively. HL was purified from postheparin human plasma by heparin sepharose affinity chromatography.14 Half of the TG-rich HDL was incubated with HL at 34°C for 4 hours in the presence of 2.5% BSA and 60 U/mL heparin,13,14 followed by isolation and dialysis. The lipolytically modified HDL is referred to as remnant HDL. HDL preparations were each iodinated by a modification of the iodine monochloride method,33 reisolated, and dialyzed. Specific activities of the reisolated HDL ranged from 9 to 36 cpm/ng protein.
Lipid composition of HDL was assayed using commercial kits. Particle size was determined by 4% to 30% nondenaturing PAGE.16,34 A multiplex ELISA (Linco Research, St Charles, Mo) was used to quantify apolipoproteins. Lysophosphatidylcholine species were analyzed by electrospray tandem mass spectrometry using a Sciex API 4000 instrument.35 An immunoaffinity chromatography method was used to separate apoA-I only and apoA-I/A-II particles of labeled HDL.16,34 Labeled HDL were subjected to isoelectrofocusing,36 and bands corresponding to specific apolipoproteins were excised and counted for radioactivity.
Cell Binding Assays
Cell binding assays were performed at 4°C (HepG2 and HEK293 cells) or 37°C (CHO, ldlA7, and ldlA[hSR-BI] cells) for 150 minutes, and radioactivity in cell lysate was counted. Nonspecific binding was determined using 100x unlabeled HDL and was always <40% of total binding.
Competitive Inhibition Assays
Cells were incubated with 100 µg/mL labeled remnant HDL and increasing concentrations of unlabeled ligand for 150 minutes at 4°C, and radioactivity in cell lysate was counted.
Internalization Assay
After incubation with ligands at 37°C for 150 minutes, cells were washed and further incubated with excess cold ligands at 4°C for 150 minutes, and radioactivity in cell lysate was counted.11 Nonspecific internalization was determined by adding 100x unlabeled HDL and was always <40% of the total internalization.
Degradation Assay
Cellular degradation of HDL was assessed by measuring trichloracetic acid–nonprecipitable material present in the medium.37
Western Blot Analysis
HEK293 cell lysate was analyzed by 6% SDS-PAGE under reducing conditions and immunoblotted with a primary antibody against human cubilin (1:200) (Santa Cruz Biotechnology; sc-23644) and a goat anti-rabbit secondary antibody (1:4000) conjugated with horseradish peroxidase. Detection was by enhanced chemiluminescence. Rat kidney extract (Santa Cruz Biotechnology; sc-2394) was used as positive control. Western blotting of human SR-BI was as previously described.38
Statistics
Results are presented as means±SEM. Binding and competition assays were analyzed using Prism (v3.03, GraphPad, San Diego, Calif). F tests were performed in Prism to compare fitting of the binding data to 1 or 2 classes of binding sites. Time- or concentration-dependent data were analyzed by ANOVA with Tukey’s post hoc test. Student’s unpaired t test was used to compare kinetic parameters or effects between different HDL preparations. A probability value of <0.05 was considered significant.
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Results |
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Modification of HDL Particle Composition by Preincubation With VLDL and HL Hydrolysis
Ex vivo incubation of human plasma with VLDL significantly enriched HDL particles with TG by
2-fold, with concomitant reduction in both cholesterol and phospholipids (Table), as was the case previously with HDL isolated from hypertriglyceridemic individuals39 and from subjects who received an IV infusion of Intralipid and heparin to enrich HDL with TG in vivo.16 HL hydrolysis of TG-rich HDL reduced the TG content without significantly altering the mass percentage of other components, consistent with ex vivo hydrolysis of rabbit HDL14 and HDL isolated from subjects following in vivo stimulation of lipolysis by IV heparin injection.40,41 TG enrichment after incubation with VLDL also yielded larger particles, whereas HL hydrolysis tended to decrease the particle size as compared to TG-rich HDL. ApoA-I and apoA-II accounted for the majority of protein and their relative contribution by mass to the total protein was not significantly affected by TG enrichment or HL hydrolysis. ApoCII and apoCIII were both reduced in TG-rich HDL, and their relative quantity in HDL was not further modified by HL. Remnant HDL had lower apoE compared to other HDL species. Among the lysophosphatidylcholine species, those with unsaturated fatty acids (18:2, 20:4, 22:5, and 22:6) were relatively increased in remnant HDL (Figure 1A). Lysophosphatidylcholines with 18:0 were also increased in both TG-rich and remnant HDL because of transfer of 18:0 and TG from VLDL during the TG enrichment (Figure 1B).
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P<0.05 vs TG-rich; ¶P<0.01 vs TG-rich.
Binding of Native, TG-Rich, or Remnant HDL in HepG2 and HEK293 Cells
Binding of HDL in both cell lines exhibited concentration dependence with increased binding of remnant HDL compared to native and TG-rich HDL (Figure 2A and 2C). The maximal binding of remnant HDL was greater than that of either TG-rich or native HDL (P<0.001 in HepG2 cells and P<0.0001 in HEK293 cells). Binding affinity was similar for all ligands in HepG2 cells, whereas it was lower for remnant than for native or TG-rich HDL in HEK293 cells (P<0.05). Bmax and Kd were similar between native and TG-rich HDL in both cell types. F tests of the binding suggested no more than one binding site was needed to account for the binding kinetics. Scatchard analysis of the binding kinetics suggested a common binding site for all HDL ligands in both cell types (Figure 2B and 2D).
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Competitive Inhibition of Remnant HDL Binding by Native, TG-Rich, or Remnant HDL in HepG2 and HEK293 Cells
Labeled remnant HDL binding was inhibited by unlabeled ligands in a concentration-dependent fashion (Figure 3A and 3B). Inhibition of labeled remnant HDL binding exhibited similar patterns by these 3 unlabeled ligands, ie, unlabeled native, TG-rich, or remnant HDL equally displaced labeled remnant bound to both cell types, demonstrating similar binding affinity and likely common binding site of all HDL species.
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Cellular Internalization of Native, TG-Rich, or Remnant HDL in HepG2 and HEK293 Cells
In both HepG2 and HEK293 cells, total internalization was greater for remnant HDL than for native and TG-rich HDL (Figure 4A and 4B). For instance, at the highest concentrations measured, compared with native and TG-rich HDL, internalization of remnant HDL was 1.7- and 2.1-fold higher in HepG2 cells and 2.3- and 1.6-fold higher in HEK293 cells.
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Cellular Degradation of Native, TG-Rich, or Remnant HDL in HepG2 and HEK293 Cells
HDL degradation was considerably higher in HEK293 cells than in HepG2 cells. At 180 µg/mL, degradation of native or TG-rich HDL was approximately double their degradation in HepG2 cells, and remnant HDL degradation was more than 3-fold higher than in HepG2 cells. In HepG2 cells, degradation of all three HDL species was similar. In contrast, remnant HDL degradation in HEK293 cells was greater than native or TG-rich HDL (P<0.01) (Figure 5A and 5B).
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Cellular Binding of Native, TG-Rich, or Remnant HDL in CHO, ldlA7, and ldlA[hSR-BI] Cells
Expression of human SR-BI in ldlA[hSR-BI] cells was confirmed by immunofluorescence and Western blot (Figure 6A and 6B). Binding of HDL, regardless of modifications, to SR-BI expressing cells was greater than to control cells, indicating the role of SR-BI as an HDL receptor (Figure 6C). Binding of remnant as compared to native and TG-rich HDL was greater regardless of SR-BI expression, ie, in wild-type CHO, ldlA7, and ldlA[hSR-BI] cells, suggesting that SR-BI was not responsible for the selective increase in remnant HDL binding. Because both ldlA7 cells and ldlA[hSR-BI] lack the LDL receptor, the results also suggest that the different binding properties of the HDL species are not accounted for by mediation through the LDL receptor.
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-COP is the loading control. *P<0.05 remnant vs native and TG-rich;
Effects of Heparin Treatment on Cellular Binding of Native, TG-Rich, or Remnant HDL in HepG2 Cells
At low concentration (100 µg/mL), heparin selectively blocks lipoprotein binding to heparin sulfate proteoglycan (HSPG),42 but not to the members of the LDL receptor family or other lipoprotein receptors.43 At high concentration (5 mg/mL), heparin blocks apoE receptor–mediated lipoprotein binding to cells.43 Treatment of cells with heparin did not abolish the enhanced binding of remnant HDL to HepG2 cells (Figure 6D). Disruption of HSPG using heparinase yielded similar results (not shown). These results suggest that enhanced binding of remnant HDL cannot be accounted for by a process mediated by cell surface HSPGs or apoE receptors.
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Discussion |
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In the present study, we have shown that remnant HDL, ie, HDL particles that were first incubated with VLDL to allow exchange of lipids, and subsequently exposed to lipolytically active HL, exhibited higher binding capacity and internalization as compared with TG-rich and native HDL in liver and kidney cells and increased degradation in kidney cells. In several highly prevalent clinical scenarios, including the metabolic syndrome and type 2 diabetes, plasma concentrations of HDL-c and apoA-I are low.4,44 This is in large part attributed to enhanced HDL clearance, rather than reduced production.5 Under such conditions, HDL particles undergo extensive intravascular remodeling, including enrichment with TG and enhanced lipolysis by HL, whose activity is also increased in these metabolic states.8 Endothelial lipase is also elevated in insulin resistance45 and likely also plays an important role in HDL remodeling.46 In previous in vivo studies, we have demonstrated that both ex vivo14 and in vivo15,40 lipolysis of TG-rich HDL by HL enhances HDL clearance from the circulation. TG-rich HDL is cleared more rapidly than TG-poor HDL in healthy humans16 but not in those with functionally defective HL.47 In the New Zealand white rabbit, an animal model naturally deficient in HL activity, TG enrichment of HDL per se, in the absence of HL, is insufficient to enhance HDL clearance.13 Collectively, these findings suggest that TG enrichment of HDL, combined with HL hydrolysis, is associated with enhanced HDL clearance in vivo. The present study provides in vitro evidence that remodeling of TG-enriched HDL by HL may promote HDL catabolism via enhanced binding to hepatic and renal cells.
The increased binding and internalization of remnant HDL was not attributable to a disproportionate enrichment of the particles with specific apolipoproteins after incubating with VLDL, because there was no difference between the HDL species used in our experiments with respect to their relative quantity of iodinated apolipoproteins (Figure I in the online data supplement). In addition, HL hydrolysis of the particle without prior TG enrichment and other compositional modifications that resulted from incubation with VLDL was insufficient to enhance binding and internalization, because hydrolysis of native HDL did not promote cell binding (supplemental Figure II). This latter experiment also demonstrates that any residual HL in the HDL fractions used in the binding experiments did not account for the enhanced binding of remnants through HL ligand binding activity. Thus, we have demonstrated in vitro, in accordance with our previous in vivo studies in rabbit,14,15 that both the prior exchange of lipids between HDL and VLDL and the subsequent lipolysis of HDL by HL are necessary to promote HDL cellular binding and clearance. Furthermore, all 3 HDL species used in our experiments contained a similar proportion of labeled lipoprotein AI/AII particles (66% in native, 62% in TG-rich, and 63% in remnant HDL), and the relative radioactivity of individual apolipoproteins did not differ between the three HDL species (supplemental Figure I). Remnant HDL had relatively greater long-chain fatty acids in lysophosphatidylcholine, particularly polyunsaturated fatty acids. It has been proposed that HDL that contain a greater proportion of polyunsaturated fatty acids in lysophosphatidylcholine may have impaired capacity for reverse cholesterol transport.48
It would be informative if remnant HDL particles could be isolated directly from insulin resistant or hypertriglyceridemic subjects, to determine their precise composition and to test whether they behave in a pattern similar to that observed in our experimental system. Not only is it presently not technically possible to physically separate remnant HDL particles from nonremnant HDL species in human plasma but their more rapid clearance from the circulation in humans who have hypertriglyceridemia and higher HL activity would tend to relatively deplete the remnant HDL fraction, making them harder to isolate. In addition, endothelial lipase is also increased in these conditions45,49; thus, HDL from these subjects would likely result from more complex vascular remodeling.
Remnant HDL was degraded to a greater extent in HEK293 cells than native and TG-rich HDL, which is in agreement with the finding that the kidney is the major site of HDL apoAI catabolism.17,22 The greater degradation of remnant HDL provides a possible explanation of HDL lowering in vivo. In monkeys made hypertriglyceridemic through inhibition of lipoprotein lipase, the increased catabolic rate of apoA-I was associated with increased renal catabolism.50 HDL isolated from humans with low HDL-c, or from humans with high HDL-c but enriched with TG and lipolytically modified, exhibited higher apoA-I accumulation in perfused rabbit kidney.51 In our experiments, HDL was degraded to a much lesser extent in HepG2 cells than in HEK293 cells. This may reflect the mechanism of retroendocytosis, where HDL holoparticle uptake is followed by recycling of HDL particles back to the cell surface and resecretion of cholesteryl ester–poor HDL, leading to net uptake of lipids.52,53
We excluded several factors as playing a role in the enhanced binding of remnant HDL, including SR-BI, the LDL receptor, cell surface HSPGs, or apoE-mediated HDL binding. SR-BI plays a pivotal role in HDL cholesteryl ester selective uptake in the liver.19,20 Our results in ldlA7 and ldlA[hSR-BI] cells indicate that remnant HDL binding is not preferentially increased in SR-BI overexpressing versus low SR-BI–expressing cells, suggesting that SR-BI does not account for the greater binding of HDL remnants compared to native or TG-rich HDL particles. HDL particles can acquire apoE and are ligands for the LDL receptor and other apoE receptors.54 Because the increased binding of remnant versus native and TG-rich HDL was observed in LDL receptor deficient cells, with a similar pattern of binding as was seen in HepG2 and HEK293 cells, it is unlikely that the increased binding of remnant HDL is mediated by the LDL receptor. The enhanced remnant binding was also not abolished by blocking of apoE-mediated HDL binding or by disruption of cell surface HSPGs in HepG2 cells. Cubilin expression in HEK293 cells in the present culture conditions was not detected using Western blot (supplemental Figure III), and it is not expressed in HepG2 cells.55 Therefore, the enhanced binding of remnant HDL cannot be attributed to cubilin. We speculate that the enhanced binding of remnant HDL may not be attributable to a single factor; rather, it might be the amalgamated result of a series of events, such as modified lipid content and apolipoprotein composition, changes in particle size, surface charge, and HDL particle interaction with cell surface receptors. This is not surprising, considering the heterogeneous nature of the HDL particles and continuous remodeling of HDL particles in vivo. Precisely which receptor(s) plays a major role in binding and internalizing these lipolytically modified, TG-rich HDL particles will require further study.
In summary, the present studies have extended our previous in vivo observations to demonstrate that lipolytically modified TG-rich HDL have greater specific binding to and internalization in both liver cells and kidney cells and greater degradation in kidney cells, providing a biochemical mechanism for their more rapid clearance from the circulation. Further studies are needed to elucidate the nature of the HDL binding site and precisely which characteristics of the remnant HDL particles are responsible for the increased binding.
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Acknowledgments |
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We thank Dr Peixiang Wang for help with the cubilin Western blot.
Sources of Funding
This work was supported by Heart and Stroke Foundation of Ontario grant T4979 (to G.F.L.) and the NIH grant HL 086798 (to J.W.H.). G.F.L. is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and a Canada Research Chair in Diabetes (http://www.chairs.gc.ca). C.X. is supported by postdoctoral fellowships from Canadian Diabetes Association. T.V. is supported by a Pilot and Feasibility Award from the Diabetes and Endocrinology Research Center, University of Washington.
Disclosures
None.
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Footnotes |
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Original received November 21, 2007; revision received May 2, 2008; accepted June 2, 2008.
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References |
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1. Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM, Tyroler HA. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med. 1990; 322: 1700–1707.[Abstract]
2. Boden WE. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High-Density Lipoprotein Intervention Trial. Am J Cardiol. 2000; 86: 19L–22L.[Medline] [Order article via Infotrieve]
3. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 2006; 116: 3090–3100.[CrossRef][Medline] [Order article via Infotrieve]
4. Lewis GF, Steiner G. Hypertriglyceridemia and its metabolic consequences as a risk factor for atherosclerotic cardiovascular disease in non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1996; 12: 37–56.[CrossRef][Medline] [Order article via Infotrieve]
5. Rashid S, Patterson BW, Lewis GF. Thematic review series: patient-oriented research. What have we learned about HDL metabolism from kinetics studies in humans? J Lipid Res. 2006; 47: 1631–1642.
6. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005; 96: 1221–1232.
7. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 160–167.
8. Lewis GF, Murdoch S, Uffelman K, Naples M, Szeto L, Albers A, Adeli K, Brunzell JD. Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone. Diabetes. 2004; 53: 2893–2900.
9. Barrans A, Collet X, Barbaras R, Jaspard B, Manent J, Vieu C, Chap H, Perret B. Hepatic lipase induces the formation of pre-beta 1 high density lipoprotein (HDL) from triacylglycerol-rich HDL2. A study comparing liver perfusion to in vitro incubation with lipases. J Biol Chem. 1994; 269: 11572–11577.
10. Guendouzi K, Jaspard B, Barbaras R, Motta C, Vieu C, Marcel Y, Chap H, Perret B, Collet X. Biochemical and physical properties of remnant-HDL2 and of pre beta 1-HDL produced by hepatic lipase. Biochemistry. 1999; 38: 2762–2768.[CrossRef][Medline] [Order article via Infotrieve]
11. Guendouzi K, Collet X, Perret B, Chap H, Barbaras R. Remnant high density lipoprotein2 particles produced by hepatic lipase display high-affinity binding and increased endocytosis into a human hepatoma cell line (HEPG2). Biochemistry. 1998; 37: 14974–14980.[CrossRef][Medline] [Order article via Infotrieve]
12. Barbaras R, Collet X, Chap H, Perret B. Specific binding of free apolipoprotein A-I to a high-affinity binding site on HepG2 cells: characterization of two high-density lipoprotein sites. Biochemistry. 1994; 33: 2335–2340.[CrossRef][Medline] [Order article via Infotrieve]
13. Rashid S, Uffelman KD, Barrett PH, Vicini P, Adeli K, Lewis GF. Triglyceride enrichment of HDL does not alter HDL-selective cholesteryl ester clearance in rabbits. J Lipid Res. 2001; 42: 265–271.
14. Rashid S, Barrett PH, Uffelman KD, Watanabe T, Adeli K, Lewis GF. Lipolytically modified triglyceride-enriched HDLs are rapidly cleared from the circulation. Arterioscler Thromb Vasc Biol. 2002; 22: 483–487.
15. Rashid S, Trinh DK, Uffelman KD, Cohn JS, Rader DJ, Lewis GF. Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I. Circulation. 2003; 107: 3066–3072.
16. Lamarche B, Uffelman KD, Carpentier A, Cohn JS, Steiner G, Barrett PHR, Lewis GF. Triglyceride-enrichment of HDL enhances the in vivo metabolic clearance of HDL-apo A-1 in healthy men. J Clin Invest. 1999; 103: 1191–1199.[Medline] [Order article via Infotrieve]
17. Glass C, Pittman RC, Civen M, Steinberg D. Uptake of high-density lipoprotein-associated apoprotein A-I and cholesterol esters by 16 tissues of the rat in vivo and by adrenal cells and hepatocytes in vitro. J Biol Chem. 1985; 260: 744–750.
18. Steinberg D. A docking receptor for HDL cholesterol esters. Science. 1996; 271: 460–461.[CrossRef][Medline] [Order article via Infotrieve]
19. Trigatti B, Covey S, Rizvi A. Scavenger receptor class B type I in high-density lipoprotein metabolism, atherosclerosis and heart disease: lessons from gene-targeted mice. Biochem Soc Trans. 2004; 32: 116–120.[CrossRef][Medline] [Order article via Infotrieve]
20. Trigatti BL, Krieger M, Rigotti A. Influence of the HDL receptor SR-BI on lipoprotein metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 1732–1738.
21. Glass CK, Pittman RC, Keller GA, Steinberg D. Tissue sites of degradation of apoprotein A-I in the rat. J Biol Chem. 1983; 258: 7161–7167.
22. Glass C, Pittman RC, Weinstein DB, Steinberg D. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc Natl Acad Sci USA. 1983; 80: 5435–5439.
23. Hammad SM, Stefansson S, Twal WO, Drake CJ, Fleming P, Remaley A, Brewer HB, Argraves WS. Cubilin, the endocytic receptor for intrinsic factor-vitamin B(12) complex, mediates high-density lipoprotein holoparticle endocytosis. Proc Natl Acad Sci USA. 1999; 96: 10158–10163.
24. Hammad SM, Barth JL, Knaak C, Argraves WS. Megalin acts in concert with cubilin to mediate endocytosis of high density lipoproteins. J Biol Chem. 2000; 275: 12003–12008.
25. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993; 34: 1255–1274.[Medline] [Order article via Infotrieve]
26. Fidge NH. High density lipoprotein receptors, binding proteins, and ligands. J Lipid Res. 1999; 40: 187–201.
27. Moestrup SK, Kozyraki R. Cubilin, a high-density lipoprotein receptor. Curr Opin Lipidol. 2000; 11: 133–140.[CrossRef][Medline] [Order article via Infotrieve]
28. Vassiliou G, Benoist F, Lau P, Kavaslar GN, McPherson R. The low density lipoprotein receptor-related protein contributes to selective uptake of high density lipoprotein cholesteryl esters by SW872 liposarcoma cells and primary human adipocytes. J Biol Chem. 2001; 276: 48823–48830.
29. Hidaka H, Fidge NH. Affinity purification of the hepatic high-density lipoprotein receptor identifies two acidic glycoproteins and enables further characterization of their binding properties. Biochem J. 1992; 284 (pt 1): 161–167.[Medline] [Order article via Infotrieve]
30. McKnight GL, Reasoner J, Gilbert T, Sundquist KO, Hokland B, McKernan PA, Champagne J, Johnson CJ, Bailey MC, Holly R. Cloning and expression of a cellular high density lipoprotein-binding protein that is up-regulated by cholesterol loading of cells. J Biol Chem. 1992; 267: 12131–12141.
31. Ritter M, Buechler C, Boettcher A, Barlage S, Schmitz-Madry A, Orso E, Bared SM, Schmiedeknecht G, Baehr CH, Fricker G, Schmitz G. Cloning and characterization of a novel apolipoprotein A-I binding protein, AI-BP, secreted by cells of the kidney proximal tubules in response to HDL or ApoA-I. Genomics. 2002; 79: 693–702.[CrossRef][Medline] [Order article via Infotrieve]
32. Martinez LO, Jacquet S, Esteve JP, Rolland C, Cabezon E, Champagne E, Pineau T, Georgeaud V, Walker JE, Terce F, Collet X, Perret B, Barbaras R. Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature. 2003; 421: 75–79.[CrossRef][Medline] [Order article via Infotrieve]
33. McFarlane AS. Efficient trace labelling of proteins with iodine. Nature. 1958; 182: 53.[Medline] [Order article via Infotrieve]
34. Li Z, McNamara JR, Ordovas JM, Schaefer EJ. Analysis of high density lipoproteins by a modified gradient gel electrophoresis method. J Lipid Res. 1994; 35: 1698–1711.[Abstract]
35. Liebisch G, Drobnik W, Lieser B, Schmitz G. High-throughput quantification of lysophosphatidylcholine by electrospray ionization tandem mass spectrometry. Clin Chem. 2002; 48: 2217–2224.
36. Batal R, Tremblay M, Krimbou L, Mamer O, Davignon J, Genest J Jr, Cohn JS. Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I. Arterioscler Thromb Vasc Biol. 1998; 18: 655–664.
37. Goldstein JL, Basu SK, Brown MS. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983; 98: 241–260.[Medline] [Order article via Infotrieve]
38. Zhang Y, Ahmed AM, Tran TL, Lin J, McFarlane N, Boreham DR, Igdoura SA, Truant R, Trigatti BL. The inhibition of endocytosis affects HDL-lipid uptake mediated by the human scavenger receptor class B type I. Mol Membr Biol. 2007; 24: 442–454.[CrossRef][Medline] [Order article via Infotrieve]
39. Lamarche B, Uffelman KD, Steiner G, Barrett PH, Lewis GF. Analysis of particle size and lipid composition as determinants of the metabolic clearance of human high density lipoproteins in a rabbit model. J Lipid Res. 1998; 39: 1162–1172.
40. Lewis GF, Lamarche B, Uffelman KD, Heatherington AC, Honig MA, Szeto LW, Barrett PH. Clearance of postprandial and lipolytically modified human HDL in rabbits and rats. J Lipid Res. 1997; 38: 1771–1778.[Abstract]
41. Lewis GF, Uffelman KD, Lamarche B, Cabana VG, Getz GS. Production of small high-density lipoprotein particles after stimulation of in vivo lipolysis in hypertriglyceridemic individuals: studies before and after triglyceride-lowering therapy. Metabolism. 1998; 47: 234–242.[CrossRef][Medline] [Order article via Infotrieve]
42. Fuki IV, Blanchard N, Jin W, Marchadier DH, Millar JS, Glick JM, Rader DJ. Endogenously produced endothelial lipase enhances binding and cellular processing of plasma lipoproteins via heparan sulfate proteoglycan-mediated pathway. J Biol Chem. 2003; 278: 34331–34338.
43. Goldstein JL, Basu SK, Brunschede GY, Brown MS. Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans. Cell. 1976; 7: 85–95.[CrossRef][Medline] [Order article via Infotrieve]
44. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999; 341: 410–418.
45. Badellino KO, Wolfe ML, Reilly MP, Rader DJ. Endothelial lipase concentrations are increased in metabolic syndrome and associated with coronary atherosclerosis. PLoS Med. 2006; 3: e22.[CrossRef][Medline] [Order article via Infotrieve]
46. Badellino KO, Rader DJ. The role of endothelial lipase in high-density lipoprotein metabolism. Curr Opin Cardiol. 2004; 19: 392–395.[CrossRef][Medline] [Order article via Infotrieve]
47. Ruel IL, Couture P, Cohn JS, Bensadoun A, Marcil M, Lamarche B. Evidence that hepatic lipase deficiency in humans is not associated with proatherogenic changes in HDL composition and metabolism. J Lipid Res. 2004; 45: 1528–1537.
48. Marmillot P, Patel S, Lakshman MR. Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins. Metabolism. 2007; 56: 251–259.[CrossRef][Medline] [Order article via Infotrieve]
49. Badellino KO, Wolfe ML, Reilly MP, Rader DJ. Endothelial lipase is increased in vivo by inflammation in humans. Circulation. 2008; 117: 678–685.
50. Goldberg IJ, Blaner WS, Vanni TM, Moukides M, Ramakrishnan R. Role of lipoprotein lipase in the regulation of high density lipoprotein apolipoprotein metabolism. Studies in normal and lipoprotein lipase-inhibited monkeys. J Clin Invest. 1990; 86: 463–473.[Medline] [Order article via Infotrieve]
51. Horowitz BS, Goldberg IJ, Merab J, Vanni TM, Ramakrishnan R, Ginsberg HN. Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol. J Clin Invest. 1993; 91: 1743–1752.[Medline] [Order article via Infotrieve]
52. DeLamatre JG, Sarphie TG, Archibold RC, Hornick CA. Metabolism of apoE-free high density lipoproteins in rat hepatoma cells: evidence for a retroendocytic pathway. J Lipid Res. 1990; 31: 191–202.[Abstract]
53. Silver DL, Wang N, Xiao X, Tall AR. High density lipoprotein (HDL) particle uptake mediated by scavenger receptor class B type 1 results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion. J Biol Chem. 2001; 276: 25287–25293.
54. Mahley RW, Huang Y, Weisgraber KH. Putting cholesterol in its place: apoE and reverse cholesterol transport. J Clin Invest. 2006; 116: 1226–1229.[CrossRef][Medline] [Order article via Infotrieve]
55. Erranz B, Miquel JF, Argraves WS, Barth JL, Pimentel F, Marzolo MP. Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids. J Lipid Res. 2004; 45: 2185–2198.
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