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• W2022890012 abstract "Hepatic lipase (HL) on the surface of hepatocytes and endothelial cells lining hepatic sinusoids, the adrenal glands, and the ovary hydrolyzes triglycerides and phospholipids of circulating lipoproteins. Its expression significantly enhances low density lipoprotein (LDL) uptake via the LDL receptor pathway. A specific interaction between LPL, a homologous molecule to HL, and apoB has been described (Choi, S. Y., Sivaram, P., Walker, D. E., Curtiss, L. K., Gretch, D. G., Sturley, S. L., Attie, A. D., Deckelbaum, R. J., and Goldberg, I. J. (1995) J. Biol. Chem. 270, 8081–8086). The present studies tested the hypothesis that HL enhances the uptake of lipoproteins by a specific interaction of HL with apoB. On a ligand blot, HL bound to apoB26, 48, and 100 but not to apoE or apoAI. HL binding to LDL in a plate assay with LDL-coated plates was significantly greater than to bovine serum albumin-coated plates. Neither heat denatured HL nor bacterial fusion protein of HL bound to LDL in the plate assays. 125I-LDL bound to HL-saturated heparin-agarose gel with a Kdof 52 nm, and somewhat surprisingly, this binding was not inhibited by excess LPL. In cell culture experiments HL enhanced the uptake of 125I-LDL at both 4 and 37 °C. The enhanced binding and uptake of LDL was significantly inhibited by monoclonal anti-apoB antibodies. In contrast to LPL, both amino- and carboxyl-terminal antibodies blocked the apoB interaction with HL to the same extent. Thus, we conclude that there is a unique interaction between HL and apoB that facilitates the uptake of apoB-containing lipoproteins by cells where HL is present. Hepatic lipase (HL) on the surface of hepatocytes and endothelial cells lining hepatic sinusoids, the adrenal glands, and the ovary hydrolyzes triglycerides and phospholipids of circulating lipoproteins. Its expression significantly enhances low density lipoprotein (LDL) uptake via the LDL receptor pathway. A specific interaction between LPL, a homologous molecule to HL, and apoB has been described (Choi, S. Y., Sivaram, P., Walker, D. E., Curtiss, L. K., Gretch, D. G., Sturley, S. L., Attie, A. D., Deckelbaum, R. J., and Goldberg, I. J. (1995) J. Biol. Chem. 270, 8081–8086). The present studies tested the hypothesis that HL enhances the uptake of lipoproteins by a specific interaction of HL with apoB. On a ligand blot, HL bound to apoB26, 48, and 100 but not to apoE or apoAI. HL binding to LDL in a plate assay with LDL-coated plates was significantly greater than to bovine serum albumin-coated plates. Neither heat denatured HL nor bacterial fusion protein of HL bound to LDL in the plate assays. 125I-LDL bound to HL-saturated heparin-agarose gel with a Kdof 52 nm, and somewhat surprisingly, this binding was not inhibited by excess LPL. In cell culture experiments HL enhanced the uptake of 125I-LDL at both 4 and 37 °C. The enhanced binding and uptake of LDL was significantly inhibited by monoclonal anti-apoB antibodies. In contrast to LPL, both amino- and carboxyl-terminal antibodies blocked the apoB interaction with HL to the same extent. Thus, we conclude that there is a unique interaction between HL and apoB that facilitates the uptake of apoB-containing lipoproteins by cells where HL is present. Hepatic lipase is synthesized in hepatic parenchymal cells and functions primarily as an endothelial bound enzyme within the liver sinusoids (1Jensen G.L. Baly D.L. Brannon P.M. Bensadoun A. J. Biol. Chem. 1980; 255: 11141-11148Abstract Full Text PDF PubMed Google Scholar, 2Doolittle M.H. Wong H. Davis R.C. Schotz M.C. J. Lipid Res. 1987; 28: 1326-1334Abstract Full Text PDF PubMed Google Scholar, 3Jansen H. van Berkel T.J. Hulsmann W.C. Biochim. Biophys. Acta. 1980; 619: 119-128Crossref PubMed Scopus (15) Google Scholar), although some enzyme is found in adrenal glands and the ovaries (4Jansen H. de Greef W.J. Biochem J. 1981; 196: 739-745Crossref PubMed Scopus (64) Google Scholar). The enzyme hydrolyzes triglycerides and phospholipids of the circulating lipoproteins; thus, it is involved in the metabolism of high density lipoproteins (HDL) 1The abbreviations used are: HDLhigh density lipoproteinLDLlow density lipoproteinLPLlipoprotein lipaseapoapolipoproteinCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresisBSAbovine serum albuminTBSTris-buffered salinemAbmonoclonal antibodyHLhepatic lipase.1The abbreviations used are: HDLhigh density lipoproteinLDLlow density lipoproteinLPLlipoprotein lipaseapoapolipoproteinCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresisBSAbovine serum albuminTBSTris-buffered salinemAbmonoclonal antibodyHLhepatic lipase. converting the HDL2 fraction to HDL3 and in the conversion of intermediate density lipoprotein to low density lipoprotein (LDL).Several lines of evidence now suggest that hepatic lipase may play another role in the metabolism of apoB-containing lipoproteins. In vivo inhibition of hepatic lipase, with an antibody to the protein, delays the clearance of chylomicron remnants (5de Faria E. Fong L.G. Komaromy M. Cooper A.D. J. Lipid Res. 1996; 37: 197-209Abstract Full Text PDF PubMed Google Scholar), and patients with hepatic lipase deficiency often have an accumulation of remnant-like lipoproteins in the plasma. Overexpression of hepatic lipase in transgenic rabbits results in reduced levels of plasma HDL and intermediate density lipoprotein (6Fan J. Wang J. Bensadoun A. Lauer S.J. Dang Q. Mahley R.W. Taylor J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8724-8728Crossref PubMed Scopus (216) Google Scholar). Gel filtration studies of hepatic lipase in post-heparin plasma revealed that hepatic lipase is associated with lipoproteins that overlap the elution of small LDL (7Goldberg I.J. Kandel J.J. Blum C.B. Ginsberg H.N. J. Clin. Invest. 1986; 78: 1523-1528Crossref PubMed Scopus (55) Google Scholar). Furthermore, it was demonstrated by this laboratory (8Choi S.Y. Komaromy M.C. Chen J. Fong L.G. Cooper A.D. J. Lipid Res. 1994; 35: 848-859Abstract Full Text PDF PubMed Google Scholar) that hepatic lipase significantly enhanced LDL uptake via the LDL receptor pathway in Chinese hamster ovary (CHO) cells transfected with rat hepatic lipase cDNA. The amount of the LDL receptor was virtually identical in the transfected cells as compared with the control cells; thus, the presence of hepatic lipase enhanced the affinity of the lipoprotein particle for the LDL receptor. Recently, Krapp et al. (9Krapp A. Ahlem S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. J. Lipid Res. 1996; 37: 926-936Abstract Full Text PDF PubMed Google Scholar) reported that hepatic lipase mediates the uptake of apoE-containing lipoproteins via LDL receptor-related protein.The mechanisms whereby hepatic lipase facilitates the metabolism of plasma lipoproteins have not been elucidated. One study (10Aviram M. Bierman E.L. Chait A. J. Biol. Chem. 1988; 263: 15416-15422Abstract Full Text PDF PubMed Google Scholar) suggested that hydrolysis of the lipid core by the enzyme facilitates the uptake of lipoproteins. However, a number of recent reports (9Krapp A. Ahlem S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. J. Lipid Res. 1996; 37: 926-936Abstract Full Text PDF PubMed Google Scholar) suggest that nonenzymatic functions of hepatic lipase facilitate the uptake of plasma lipoproteins through an interaction between cell surface heparan sulfate proteoglycans and the apoB of lipoprotein particles. An association of lipoprotein lipase (LPL) with apoB-containing lipoproteins by a specific protein-protein interaction between LPL and apoB was recently reported by Choi et al. (11Choi S.Y. Sivaram P. Walker D.E. Curtiss L.K. Gretch D.G. Sturley S.L. Attie A.D. Deckelbaum R.J. Goldberg I.J. J. Biol. Chem. 1995; 270: 8081-8086Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Analysis of amino acid sequences of hepatic lipase and LPL has shown that there is an extensive amino acid homology between these lipases (12Hide W.A. Chan L. Li W-H. J. Lipid Res. 1992; 33: 167-178Abstract Full Text PDF PubMed Google Scholar). Additionally, both LPL and hepatic lipase bind to proteoglycans (13Hayden M.R. Ma Y. Brunzell J. Henderson H.E. Curr. Opin. Lipodol. 1991; 2: 104-109Crossref Scopus (43) Google Scholar). Thus, the present studies were designed to test the hypothesis that a nonenzymatic function of hepatic lipase may facilitate the uptake of apoB-containing lipoproteins.DISCUSSIONThe present experiments provide strong support for the hypothesis that an interaction between hepatic lipase and apoB facilitates the uptake of apoB-containing lipoproteins. There had been considerable evidence suggesting that hepatic lipase plays a role in the removal of apoB-containing lipoproteins (5de Faria E. Fong L.G. Komaromy M. Cooper A.D. J. Lipid Res. 1996; 37: 197-209Abstract Full Text PDF PubMed Google Scholar, 25Breckenridge W.C. Atherosclerosis. 1982; 45: 161-179Abstract Full Text PDF PubMed Scopus (231) Google Scholar, 26Murase T. Itakura H. Atherosclerosis. 1981; 39: 293-300Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 27Goldberg I.J. Le N.A. Pataerniti Jr., L.R. Ginsberg H.N. Lindgren F.T. Brown W.V. J. Clin. Invest. 1982; 70: 114-1192Crossref Scopus (174) Google Scholar, 28Shafi S. Brady S.E. Bensadoun A. Havel R.J. J. Lipid Res. 1994; 35: 709-720Abstract Full Text PDF PubMed Google Scholar). This could be due to the lipolytic activity of the enzyme causing remodeling of the particles allowing enhanced uptake, as has been suggested by Aviram et al. (10Aviram M. Bierman E.L. Chait A. J. Biol. Chem. 1988; 263: 15416-15422Abstract Full Text PDF PubMed Google Scholar); alternatively, however, the recent evidence that lipoprotein lipase facilitates LDL uptake by binding LDL led us to explore this as a possible mechanism of hepatic lipase action.Evidence for a direct interaction of apoB with hepatic lipase was provided by ligand blots, solid phase and solution assays, and cell culture experiments. On a ligand blot, hepatic lipase bound to several forms of apoBs including B48 and B100 and the kallikrein cleavage products of apoB100, B26, and B74 (29Cardin A.D. Witt K.R. Chao J. Margolius H.S. Donaldson V.H. Jackson R.L. J. Biol. Chem. 1984; 259: 8522-8528Abstract Full Text PDF PubMed Google Scholar) present on lipoproteins but not to other apolipoproteins including apoE and apoAI. The interaction between apoB and hepatic lipase was further studied by solid phase and solution assays. In a solution assay, where hepatic lipase was in excess, LDL binding to hepatic lipase clearly shows saturation kinetics with a Kd of 52.86 nm. In a solid phase assay with apoB in excess, the requirement for the hepatic lipase secondary and/or tertiary structure was demonstrated. The functional significance of the interaction was demonstrated in cell culture where monoclonal antibodies against apoB on both the amino- and carboxyl-terminal regions inhibited the hepatic lipase-mediated LDL uptake. Lastly, LDL binding to hepatic lipase-saturated agarose gel was not inhibited by the presence of excess LPL, suggesting that these proteins bind to distinct regions of apoB.ApoB100 is a large glycoprotein with a molecular mass of 550 kDa and is virtually the only protein component of LDL particles. The carboxyl-terminal region of apoB is involved in binding to LDL receptors, and this region also contains five of seven apoB heparin binding sites (30Weisgraber K.H. Rall Jr., S.C. J. Biol. Chem. 1987; 262: 11097-11103Abstract Full Text PDF PubMed Google Scholar). Under physiologic ionic conditions, however, LDL binds weakly to heparin (31Iverius P.-H. J. Biol. Chem. 1972; 247: 2607-2613Abstract Full Text PDF PubMed Google Scholar). The amino-terminal region of apoB is hydrophilic and thought to be a globular structure that extends away from the lipid core of lipoproteins (32Chan L. J. Biol. Chem. 1992; 267: 25621-25624Abstract Full Text PDF PubMed Google Scholar). Possible functions of the amino-terminal region of apoB have recently been elucidated (33Ingram M.F. Shelness G.S. J. Biol. Chem. 1997; 272: 10279-10286Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 34Kreuzer J. Whiter A.L. Knott T.J. Jien M-L. Mehrabian M. Scott J. Young S.G. Haberland M.E. J. Lipid Res. 1997; 38: 324-342Abstract Full Text PDF PubMed Google Scholar, 35Gretch D.G. Sturley S.L. Wang L. Lipton B.A. Dunning A. Grunnwald K.A. Wetterau J.R. Yao Z. Talmud P. Attie A.D. J. Biol. Chem. 1996; 271: 8682-8691Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Using monoclonal antibodies against amino and carboxyl regions of apoB we recently demonstrated that the amino-terminal, but not the carboxyl-terminal, region of apoB interacts with LPL (36Sivaram P. Choi S.Y. Curtiss L.K. Goldberg I.J. J. Biol. Chem. 1994; 269: 9409-9412Abstract Full Text PDF PubMed Google Scholar). In contrast to LPL, the present experiments suggest that both the amino and carboxyl regions of apoB have binding domains for hepatic lipase. Evidence supporting this was provided primarily by solid phase assays in which the binding of LDL to hepatic lipase-expressing CHO cells or purified hepatic lipase, respectively, was inhibited by both carboxyl- and amino-terminal anti-apoB antibodies (i.e. mAb47 and mAb3, respectively). Ligand blots using thrombin-digested apoB also showed that hepatic lipase bound to both amino- and carboxyl-terminal fragments of apoB (data not shown).The cell culture studies provide strong support for the concept that the interaction between apoB and hepatic lipase is of physiologic significance. In cell culture both antibodies also decreased LDL binding to cells that secreted hepatic lipase. Interpretation of the result with mAb3 is straight forward; its ability to eliminate the increment of binding due to the secretion of hepatic lipase supports the hypothesis that the hepatic lipase effect is due to an interaction with apoB. mAb47, however, binds to an epitope near the LDL receptor binding domain of apoB. Accordingly, its effect could be due to direct interference with the receptor-ligand interaction. Consistent with this was its ability to decrease cell association and degradation in control cells as well as in hepatic lipase-transfected cells. Interestingly, in the binding studies the antibody did not completely inhibit binding in either cell line but reduced binding in HL secretors to that of nonsecretors. Thus, if its main effect on LDL processing is on internalization, the effect on binding to the secretor could be due to elimination of the apoB-HL interaction. This requires further exploration. Taking the cell culture and solid phase assay data together, however, it appears that there are hepatic lipase binding sites on both the amino-terminal region of apoB and in the region near the LDL receptor binding domain.Earlier studies have clearly demonstrated the role of hepatic lipase in remodeling larger lipoproteins such as intermediate density lipoprotein and HDL2 into the smaller particles, LDL and HDL3, respectively. The lipolytic activity, however, may not be required for the facilitation of lipoprotein uptake by tissues. First, a previous in vivo study showed that, in mice, injection of anti-rat hepatic lipase antibody resulted in a small but significant reduction in the rate of chylomicron remnant removal from plasma (5de Faria E. Fong L.G. Komaromy M. Cooper A.D. J. Lipid Res. 1996; 37: 197-209Abstract Full Text PDF PubMed Google Scholar); however, the antibodies did not inhibit lipolysis by mouse hepatic lipase, suggesting that lipolysis was not the mechanism by which hepatic lipase enhanced remnant uptake. Second, in the present study the binding experiments were performed at 4 °C (Fig.4 B) to minimize lipid hydrolysis by hepatic lipase, and again, LDL binding was significantly enhanced in hepatic lipase-expressing cell lines, suggesting that a nonenzymatic function of hepatic lipase played a role in lipoprotein uptake. Further, the presence of phenylmethylsulfonyl fluoride (100 μm), an inhibitor of lipolytic activity, did not reduce the binding of hepatic lipase to LDL in solid phase assays. This is consistent with an expanding body of evidence that LPL, a closely related enzyme, does not require its catalytic activity for its interaction with LDL. Future experiments with active-site mutant proteins should help to elucidate this definitively.Possible nonenzymatic mechanisms of action of hepatic lipase include bridging of lipoproteins and heparan sulfate proteoglycans. Previously, it was demonstrated that hepatic lipase enhanced the uptake of LDL in CHO cells transfected with rat hepatic lipase cDNA and that anti-LDL receptor antibodies virtually eliminated the hepatic lipase-mediated LDL uptake (8Choi S.Y. Komaromy M.C. Chen J. Fong L.G. Cooper A.D. J. Lipid Res. 1994; 35: 848-859Abstract Full Text PDF PubMed Google Scholar). The amount of LDL receptor and of LDL receptor-related protein in the transfected cells was identical to that in wild-type cells on both Western and Northern blots. Furthermore, kinetic studies indicated that the increased LDL binding in the hepatic lipase-secreting CHO cells was the result of a higher affinity of the particle for the LDL receptor. Together, these data suggest that hepatic lipase enhanced the uptake of LDL via the LDL receptor-mediated pathway by increasing its affinity for the receptor.A number of previous studies have suggested that lipoprotein lipase can anchor lipoproteins to cell surface and matrix proteoglycans (37Saxena U. Klein M.G. Vanni T.M. Goldberg I.J. J. Clin. Invest. 1992; 89: 373-380Crossref PubMed Scopus (123) Google Scholar, 38Eisenberg S. Sehayek E. Olivecrona T. Vlodavsky I. J. Clin. Invest. 1992; 90: 2013-2021Crossref PubMed Scopus (192) Google Scholar), and this molecular bridge has been postulated to increase lipoprotein retention by subendothelial cell matrix and increase cellular lipoprotein uptake. Similarly it has been suggested (39Ji Z.S. Lauer S.J. Fazio S. Bensadoun A. Taylor J.M. Mahley R.W. J. Biol. Chem. 1994; 269: 13429-13436Abstract Full Text PDF PubMed Google Scholar) that hepatic lipase binding to lipoproteins requires heparan sulfate proteoglycans, and it was recently reported (9Krapp A. Ahlem S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. J. Lipid Res. 1996; 37: 926-936Abstract Full Text PDF PubMed Google Scholar) that hepatic lipase mediates the uptake of apoE-containing lipoproteins via the LDL receptor-related protein and that this effect was absent in proteoglycan deficient cells.Based on the present study we propose that hepatic lipase enhances the uptake of apoB-containing lipoproteins by binding both to the cell surface, presumably to heparan sulfate proteoglycans, and to apoB. Thus, hepatic lipase functions as a bridge. This could both facilitate hydrolysis of lipoproteins and increase their uptake via the LDL receptor by providing high affinity multifooted binding. Kinetic analysis suggests this is a plausible explanation.In our previous experiments (8Choi S.Y. Komaromy M.C. Chen J. Fong L.G. Cooper A.D. J. Lipid Res. 1994; 35: 848-859Abstract Full Text PDF PubMed Google Scholar) the affinity Kd of LDL for the cell surface in wild-type CHO cells was 6.6 nmand about 10-fold higher, 0.6 nm (6 × 10−10m), to cells secreting hepatic lipase. The present studies provide support for the hypothesis that the increase in affinity is due to the polyvalent or multifooted binding created by the ability of apoB to bind to both the LDL receptor and hepatic lipase on the cell surface. Comparisons of polyvalent with monovalent binding have been carried out in studies of immunoglobulin (40Bach J-F. Bach J.-H. Antigen-Antibody Reactions In Immunology. John Wiley & Sons, Inc, New York1978: 248-286Google Scholar). It was found that IgG anti-dinitrophenyl antibodies bound to aggregated dinitrophenyl with 103 to 105greater affinity than to monomeric dinitrophenyl. This is because when multiple sites are present, the actual affinity may be much higher than the intrinsic affinity, due to the cooperation between sites. Thus even though the affinity of apoB for hepatic lipase, 52 nm, was about one-thirtieth that of LDL for the LDL receptor, which was determined to be 1.6 nm in a plate assay (41van Driel I.R. Brown M.S. Goldstein J.L. J. Biol. Chem. 1989; 264: 9533-9538Abstract Full Text PDF PubMed Google Scholar), it is highly plausible to suggest that the affinity of apoB for the multiple binding sites generated by both HL and LDL receptor was 10-fold enhanced compared with that for its binding to the LDL receptors alone. In fact the increase of 1 order of magnitude may be less than might have been expected from the immunoglobulin studies. This could be due to failure of each particle to undergo multifooted binding. It is, however, of comparable magnitude to the increase in the affinity for the LDL receptor of liposomes containing four molecules of apoE compared with those containing one molecule of apoE. We recently reported that theKd of LDL for LPL was 3.76 nm in solution assays using LPL-saturated heparin-agarose beads (42Choi S.Y. Pang L. Kern P.A. Kayden H.J. Curtiss L.K. Vanni-Reyes T.M. Goldberg I.J. J. Lipid Res. 1997; 38: 77-85Abstract Full Text PDF PubMed Google Scholar). Thus, hepatic lipase, which has a Kd of 52 nm for LDL, does not have as high an affinity as LPL. Nonetheless, these considerations illustrate how the presence of a low affinity site in the proximity of a higher affinity site, by allowing multifooted binding, may account for a considerable enhancement of LDL uptake in the organ that expresses hepatic lipase bound to its surfaces.The previous report (11Choi S.Y. Sivaram P. Walker D.E. Curtiss L.K. Gretch D.G. Sturley S.L. Attie A.D. Deckelbaum R.J. Goldberg I.J. J. Biol. Chem. 1995; 270: 8081-8086Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar) suggested that the amino-terminal region of apoB is involved in its protein-protein interaction with LPL. In contrast, hepatic lipase binds to both the amino- and carboxyl-terminal region of apoB on ligand blot. Thus, hepatic lipase binding to apoB is not identical to LPL binding to apoB, although both enzymes appear to interact with apoB by a specific protein-protein interaction. This was further supported by the somewhat surprising lack of competition between hepatic lipase and lipoprotein lipase for apoB binding. This suggests that apoB, which has numerous potential sites for protein-protein interaction in regions where it is not interacting with the lipid surface can undergo interaction with a number of molecules, and these interactions may help to define its fate. Hepatic lipase is synthesized in hepatic parenchymal cells and functions primarily as an endothelial bound enzyme within the liver sinusoids (1Jensen G.L. Baly D.L. Brannon P.M. Bensadoun A. J. Biol. Chem. 1980; 255: 11141-11148Abstract Full Text PDF PubMed Google Scholar, 2Doolittle M.H. Wong H. Davis R.C. Schotz M.C. J. Lipid Res. 1987; 28: 1326-1334Abstract Full Text PDF PubMed Google Scholar, 3Jansen H. van Berkel T.J. Hulsmann W.C. Biochim. Biophys. Acta. 1980; 619: 119-128Crossref PubMed Scopus (15) Google Scholar), although some enzyme is found in adrenal glands and the ovaries (4Jansen H. de Greef W.J. Biochem J. 1981; 196: 739-745Crossref PubMed Scopus (64) Google Scholar). The enzyme hydrolyzes triglycerides and phospholipids of the circulating lipoproteins; thus, it is involved in the metabolism of high density lipoproteins (HDL) 1The abbreviations used are: HDLhigh density lipoproteinLDLlow density lipoproteinLPLlipoprotein lipaseapoapolipoproteinCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresisBSAbovine serum albuminTBSTris-buffered salinemAbmonoclonal antibodyHLhepatic lipase.1The abbreviations used are: HDLhigh density lipoproteinLDLlow density lipoproteinLPLlipoprotein lipaseapoapolipoproteinCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresisBSAbovine serum albuminTBSTris-buffered salinemAbmonoclonal antibodyHLhepatic lipase. converting the HDL2 fraction to HDL3 and in the conversion of intermediate density lipoprotein to low density lipoprotein (LDL). high density lipoprotein low density lipoprotein lipoprotein lipase apolipoprotein Chinese hamster ovary polyacrylamide gel electrophoresis bovine serum albumin Tris-buffered saline monoclonal antibody hepatic lipase. high density lipoprotein low density lipoprotein lipoprotein lipase apolipoprotein Chinese hamster ovary polyacrylamide gel electrophoresis bovine serum albumin Tris-buffered saline monoclonal antibody hepatic lipase. Several lines of evidence now suggest that hepatic lipase may play another role in the metabolism of apoB-containing lipoproteins. In vivo inhibition of hepatic lipase, with an antibody to the protein, delays the clearance of chylomicron remnants (5de Faria E. Fong L.G. Komaromy M. Cooper A.D. J. Lipid Res. 1996; 37: 197-209Abstract Full Text PDF PubMed Google Scholar), and patients with hepatic lipase deficiency often have an accumulation of remnant-like lipoproteins in the plasma. Overexpression of hepatic lipase in transgenic rabbits results in reduced levels of plasma HDL and intermediate density lipoprotein (6Fan J. Wang J. Bensadoun A. Lauer S.J. Dang Q. Mahley R.W. Taylor J.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8724-8728Crossref PubMed Scopus (216) Google Scholar). Gel filtration studies of hepatic lipase in post-heparin plasma revealed that hepatic lipase is associated with lipoproteins that overlap the elution of small LDL (7Goldberg I.J. Kandel J.J. Blum C.B. Ginsberg H.N. J. Clin. Invest. 1986; 78: 1523-1528Crossref PubMed Scopus (55) Google Scholar). Furthermore, it was demonstrated by this laboratory (8Choi S.Y. Komaromy M.C. Chen J. Fong L.G. Cooper A.D. J. Lipid Res. 1994; 35: 848-859Abstract Full Text PDF PubMed Google Scholar) that hepatic lipase significantly enhanced LDL uptake via the LDL receptor pathway in Chinese hamster ovary (CHO) cells transfected with rat hepatic lipase cDNA. The amount of the LDL receptor was virtually identical in the transfected cells as compared with the control cells; thus, the presence of hepatic lipase enhanced the affinity of the lipoprotein particle for the LDL receptor. Recently, Krapp et al. (9Krapp A. Ahlem S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. J. Lipid Res. 1996; 37: 926-936Abstract Full Text PDF PubMed Google Scholar) reported that hepatic lipase mediates the uptake of apoE-containing lipoproteins via LDL receptor-related protein. The mechanisms whereby hepatic lipase facilitates the metabolism of plasma lipoproteins have not been elucidated. One study (10Aviram M. Bierman E.L. Chait A. J. Biol. Chem. 1988; 263: 15416-15422Abstract Full Text PDF PubMed Google Scholar) suggested that hydrolysis of the lipid core by the enzyme facilitates the uptake of lipoproteins. However, a number of recent reports (9Krapp A. Ahlem S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. J. Lipid Res. 1996; 37: 926-936Abstract Full Text PDF PubMed Google Scholar) suggest that nonenzymatic functions of hepatic lipase facilitate the uptake of plasma lipoproteins through an interaction between cell surface heparan sulfate proteoglycans and the apoB of lipoprotein particles. An association of lipoprotein lipase (LPL) with apoB-containing lipoproteins by a specific protein-protein interaction between LPL and apoB was recently reported by Choi et al. (11Choi S.Y. Sivaram P. Walker D.E. Curtiss L.K. Gretch D.G. Sturley S.L. Attie A.D. Deckelbaum R.J. Goldberg I.J. J. Biol. Chem. 1995; 270: 8081-8086Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Analysis of amino acid sequences of hepatic lipase and LPL has shown that there is an extensive amino acid homology between these lipases (12Hide W.A. Chan L. Li W-H. J. Lipid Res. 1992; 33: 167-178Abstract Full Text PDF PubMed Google Scholar). Additionally, both LPL and hepatic lipase bind to proteoglycans (13Hayden M.R. Ma Y. Brunzell J. Henderson H.E. Curr. Opin. Lipodol. 1991; 2: 104-109Crossref Scopus (43) Google Scholar). Thus, the present studies were designed to test the hypothesis that a nonenzymatic function of hepatic lipase may facilitate the uptake of apoB-containing lipoproteins. DISCUSSIONThe present experiments provide strong support for the hypothesis that an interaction between hepatic lipase and apoB facilitates the uptake of apoB-containing lipoproteins. There had been considerable evidence suggesting that hepatic lipase plays a role in the removal of apoB-containing lipoproteins (5de Faria E. Fong L.G. Komaromy M. Cooper A.D. J. Lipid Res. 1996; 37: 197-209Abstract Full Text PDF PubMed Google Scholar, 25Breckenridge W.C. Atherosclerosis. 1982; 45: 161-179Abstract Full Text PDF PubMed Scopus (231) Google Scholar, 26Murase T. Itakura H. Atherosclerosis. 1981; 39: 293-300Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 27Goldberg I.J. Le N.A. Pataerniti Jr., L.R. Ginsberg H.N. Lindgren F.T. Brown W.V. J. Clin. Invest. 1982; 70: 114-1192Crossref Scopus (174) Google Scholar, 28Shafi S. Brady S.E. Bensadoun A. Havel R.J. J. Lipid Res. 1994; 35: 709-720Abstract Full Text PDF PubMed Google Scholar). This could be due to the lipolytic activity of the enzyme causing remodeling of the particles allowing enhanced uptake, as has been suggested by Aviram et al. (10Aviram M. Bierman E.L. Chait A. J. Biol. Chem. 1988; 263: 15416-15422Abstract Full Text PDF PubMed Google Scholar); alternatively, however, the recent evidence that lipoprotein lipase facilitates LDL uptake by binding LDL led us to explore this as a possible mechanism of hepatic lipase action.Evidence for a direct interaction of apoB with hepatic lipase was provided by ligand blots, solid phase and solution assays, and cel" @default.
• W2022890012 created "2016-06-24" @default.
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• W2022890012 date "1998-08-01" @default.
• W2022890012 modified "2023-09-30" @default.
• W2022890012 title "Interaction between ApoB and Hepatic Lipase Mediates the Uptake of ApoB-containing Lipoproteins" @default.
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