In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity

Hepatic lipase (HL) is a key player in lipoprotein metabolism by modulating, through its lipolytic activity, the triglyceride (TG) and phospholipid content of apolipoprotein B (apoB)-containing lipoproteins and of high density lipoproteins (HDL), thereby affecting their size and density. A new and separate role has been suggested for HL in cellular lipoprotein metabolism, in which it serves as a ligand promoting cellular uptake of apoB-containing remnant lipoproteins and HDL. We tested the hypothesis that HL has both a lipolytic and a nonlipolytic role in human lipoprotein metabolism, by measuring lipid plasma concentrations, lipoprotein density distribution by density gradient ultracentrifugation, and lipoprotein composition, in three subjects with HL deficiency: two of the patients (S-1 and S-3) were characterized as having neither plasma HL activity nor detectable HL protein; the third subject (S-2) had no plasma HL activity but a detectable amount (35.5 ng/ml) of HL protein. All HL-deficient subjects showed a severalfold increase in lipoprotein TG content across the lipoprotein density spectrum very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and HDL as compared with control subjects. They also had remarkably more buoyant LDL particles (LDL-Rf = 0.342–0.394) as compared with the control subjects (LDL-Rf = 0.303). Subjects S-1 and S-3 (no HL activity or protein) presented with a distinct increase in cholesterol and apoB levels in the IDL and VLDL density range as compared with patient S-2, with detectable HL protein, and the control subjects. This study provides evidence in humans that HL indeed plays an important role in lipoprotein metabolism independent of its enzymatic activity: in particular, inactive HL protein appears to affect VLDL and IDL particle concentration, whereas HL enzymatic activity seems to influence VLDL-, IDL-, LDL-, and HDL-TG content and their physical properties.—Zambon, A., S. S. Deeb, A. Bensadoun, K. E. Foster, and J. D. Brunzell. In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity. J. Lipid Res. 2000. 41: 2094–2099. Hepatic lipase (HL) is a key player in lipoprotein metabolism by modulating, through its lipolytic activity, the triglyceride (TG) and phospholipid content of apolipoprotein B (apoB)-containing lipoproteins and of high density lipoproteins (HDL), thereby affecting their size and density. A new and separate role has been suggested for HL in cellular lipoprotein metabolism, in which it serves as a ligand promoting cellular uptake of apoB-containing remnant lipoproteins and HDL. We tested the hypothesis that HL has both a lipolytic and a nonlipolytic role in human lipoprotein metabolism, by measuring lipid plasma concentrations, lipoprotein density distribution by density gradient ultracentrifugation, and lipoprotein composition, in three subjects with HL deficiency: two of the patients (S-1 and S-3) were characterized as having neither plasma HL activity nor detectable HL protein; the third subject (S-2) had no plasma HL activity but a detectable amount (35.5 ng/ml) of HL protein. All HL-deficient subjects showed a severalfold increase in lipoprotein TG content across the lipoprotein density spectrum very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and HDL as compared with control subjects. They also had remarkably more buoyant LDL particles (LDL-Rf = 0.342–0.394) as compared with the control subjects (LDL-Rf = 0.303). Subjects S-1 and S-3 (no HL activity or protein) presented with a distinct increase in cholesterol and apoB levels in the IDL and VLDL density range as compared with patient S-2, with detectable HL protein, and the control subjects. This study provides evidence in humans that HL indeed plays an important role in lipoprotein metabolism independent of its enzymatic activity: in particular, inactive HL protein appears to affect VLDL and IDL particle concentration, whereas HL enzymatic activity seems to influence VLDL-, IDL-, LDL-, and HDL-TG content and their physical properties.—Zambon, A., S. S. Deeb, A. Bensadoun, K. E. Foster, and J. D. Brunzell. In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity. J. Lipid Res. 2000. 41: 2094–2099. Hepatic lipase (HL) is a 477-amino acid glycoprotein that plays a pivotal role in lipoprotein metabolism (1Brunzell J.D. Deeb S.S. Lipoprotein lipase, apo CII and hepatic lipase deficiency.in: Scriver C.R. Beaudet A. Sly W.S. Valle D. Vogelstein B. Childs B. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. McGraw-Hill, New York2000: 2789-2816Google Scholar). The human HL gene spans more than 30 kb, is composed of nine exons and eight introns (2Cai S-J. Wong D.M. Chen S-H. Chan L. Structure of the human hepatic lipase gene.Biochemistry. 1989; 28: 8966-8971Google Scholar, 3Ameis D. Stahnke G. Kobayashi J. Mclean J. Lee G. Busher M. Schotz M.C. Isolation and characterization of the human hepatic lipase gene.J. Biol. Chem. 1990; 265: 6552-6555Google Scholar), and is located on chromosome 15q21 (4Datta S. Luo C-C. Li W-H. VanTuinen P. Ledbetter D.H. Brown M.A. Chen S-H. Liu S.W. Chan L. Human hepatic lipase: cloned cDNA sequence, restriction fragment length polymorphisms, chromosomal localization, and evolutionary relationships with lipoprotein lipase and pancreatic lipase.J. Biol. Chem. 1988; 263: 1107-1110Google Scholar). The majority of HL is synthesized and secreted by the liver and is bound to heparan sulfate proteoglycans on the surfaces of sinusoidal endothelial cells and external surfaces of microvilli of parenchymal cells in the space of Disse (5Doolittle M.H. Wong H. Davis R.C. Schotz M.C. Synthesis of hepatic lipase in liver and extrahepatic tissue.J. Lipid Res. 1987; 28: 1326-1334Google Scholar, 6Sanan D.A. Fan J. Bensadoun A. Taylor J.M. Hepatic lipase is abundant on both hepatocyte and endothelial cell surfaces in the liver.J. Lipid Res. 1997; 38: 1002-1013Google Scholar). HL catalyzes the hydrolysis of triglycerides (TG) and phospholipids of intermediate density lipoprotein (IDL) remnants, large buoyant low density lipoproteins (LDL), and high density lipoproteins (HDL), resulting in smaller, more dense lipoprotein particles. HL deficiency is rare, with only 12 patients described (1Brunzell J.D. Deeb S.S. Lipoprotein lipase, apo CII and hepatic lipase deficiency.in: Scriver C.R. Beaudet A. Sly W.S. Valle D. Vogelstein B. Childs B. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. McGraw-Hill, New York2000: 2789-2816Google Scholar). The absence of HL activity leads to large buoyant, TG-enriched LDL particles (7Auwerx J. Marzetta C.A. Hokanson J.E. Brunzell J.D. Large buoyant LDL-like particles in hepatic lipase deficiency.Arteriosclerosis. 1989; 9: 319-325Google Scholar). In normal males and those with coronary artery disease (CAD) HL activity is related to decreasing size and increasing density of both HDL and LDL particles (8Zambon A. Austin M.A. Brown B.G. Hokanson J.E. Brunzell J.D. Effect of hepatic lipase on LDL in normal men and those with coronary heart disease.Arterioscler. Thromb. 1993; 13: 147-153Google Scholar). In addition to its catalytic activity as a lipase, in vitro data suggested an additional and perhaps separate role for HL in cellular lipoprotein metabolism, in which it serves as a ligand promoting cellular uptake of apolipoprotein apoB -containing remnant lipoproteins and HDL (9Santamarina-Fojo S. Haudenschild C. Amar M. The role of hepatic lipase in lipoprotein metabolism and atherosclerosis.Curr. Opin. Lipidol. 1998; 9: 211-219Google Scholar, 10Krapp A. Ahle S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP).J. Lipid Res. 1996; 37: 926-936Google Scholar, 11Huff M.W. Miller D.B. Wolfe B.M. Connelly P.W. Sawyez C.G. Uptake of hypertriglyceridmic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.J. Lipid Res. 1997; 38: 1318-1333Google Scholar, 12Ji Z.S. Dichek H.L. Miranda R.D. Mahley R.W. Heparan sulfate proteoglycans participate in hepatic lipase and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins.J. Biol. Chem. 1997; 272: 31285-31292Google Scholar). The enhancement of hepatic uptake of apoB-containing lipoproteins was independent of lipolytic activity and did not require apoE (10Krapp A. Ahle S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP).J. Lipid Res. 1996; 37: 926-936Google Scholar, 11Huff M.W. Miller D.B. Wolfe B.M. Connelly P.W. Sawyez C.G. Uptake of hypertriglyceridmic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.J. Lipid Res. 1997; 38: 1318-1333Google Scholar, 12Ji Z.S. Dichek H.L. Miranda R.D. Mahley R.W. Heparan sulfate proteoglycans participate in hepatic lipase and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins.J. Biol. Chem. 1997; 272: 31285-31292Google Scholar). These data have been confirmed by in vivo experiments showing that in transgenic mice overexpressing catalytically active human HL in the liver (13Dichek H.L. Brecht W. Fan J. Ji Z.S. McCormick S.P. Akeefe H. Conzo L. Sanan D.A. Weisgraber K.H. Young S.G. Taylor J.M. Mahley R.W. Overexpression of hepatic lipase in transgenic mice decreases apolipoprotein B-containing and high density lipoproteins. Evidence that hepatic lipase acts as a ligand for lipoprotein uptake.J. Biol. Chem. 1998; Scholar), both apoB-containing remnant lipoproteins and HDL were in mice overexpressing catalytically inactive the apoB-containing lipoproteins were but HDL was in vivo evidence Amar Haudenschild R.D. R.D. Bensadoun A. J. S. In vivo evidence of both lipolytic and nonlipolytic of hepatic lipase in the metabolism of Thromb. Biol. that both lipolytic and nonlipolytic of HL important for HDL metabolism by affecting distinct in the of HDL is no evidence of a role of HL in human lipoprotein metabolism, independent of its lipolytic activity. In the plasma lipid concentrations, lipoprotein density and lipoprotein in three subjects with HL deficiency: two of the patients were characterized as having neither plasma HL activity nor detectable HL protein; the third subject had no plasma HL activity but a detectable amount of HL protein. the hypothesis that HL human apoB-containing lipoprotein metabolism by both lipolytic and nonlipolytic in vivo evidence of a role for HL in lipoprotein metabolism in independent of a with HL was in (7Auwerx J. Marzetta C.A. Hokanson J.E. Brunzell J.D. Large buoyant LDL-like particles in hepatic lipase deficiency.Arteriosclerosis. 1989; 9: 319-325Google Scholar). is for an K. Brunzell J.D. S. A in of the lipase gene leads to resulting in Lipid Res. 1996; 37: Scholar). was to the of for and to have also low levels of plasma lipoprotein lipase activity = of acid with for a of the The patient had no deficiency as by lipolytic activity was on a which TG and plasma activity into the normal range The in were S-1 was had subjects = = lipase activity is as of is in not = in a new lipase activity is as of HL is in not a with HL was in is for the (1Brunzell J.D. Deeb S.S. Lipoprotein lipase, apo CII and hepatic lipase deficiency.in: Scriver C.R. Beaudet A. Sly W.S. Valle D. Vogelstein B. Childs B. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. McGraw-Hill, New York2000: 2789-2816Google Scholar). was in HL exons through was to the of for and to have low levels of activity of with for a of the The patient had no deficiency as by was on a with a in TG and increase in activity into the normal range The in were was had Subjects S-1 and were to the with low activity and to the of HL the two HL-deficient patients presented with and low activity, it was that HL deficiency with and normal activity more A. Brown B.G. Brunzell J.D. Hepatic lipase deficiency in a coronary artery disease Scholar). of males with and plasma apoB levels in the G. C. of coronary artery disease as a of in men with high levels of apolipoprotein J. 1990; Scholar), a third patient with HL deficiency was (1Brunzell J.D. Deeb S.S. Lipoprotein lipase, apo CII and hepatic lipase deficiency.in: Scriver C.R. Beaudet A. Sly W.S. Valle D. Vogelstein B. Childs B. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. McGraw-Hill, New York2000: 2789-2816Google Scholar, A. Brown B.G. Brunzell J.D. Hepatic lipase deficiency in a coronary artery disease Scholar). in is a with HL is for a the HL gene and had and normal activity not had a men were as control subjects. of subjects had lipid or disease affecting lipid of was the of the The study was by the human subjects of the of and was subjects. were in acid a to for lipid and density gradient for of lipoprotein cholesterol of was and was in for of HL and activity. were by and for of HL activity, activity, lipoprotein and LDL very low density lipoprotein (VLDL), HDL and apoE as as and LDL and and cholesterol were the Lipid as described A. Austin M.A. Brunzell J.D. Hokanson J.E. of LDL particles in normal subjects with LDL A and LDL Thromb. Biol. 1996; Scholar, and of high density cholesterol M.H. of Lipoprotein Scholar). gradient lipoprotein particles by the of in a density gradient and of plasma density gradient in a Lipid Res. and is to the of apoB-containing lipoproteins on described Brunzell J.D. Hokanson J.E. K. density gradient Scholar). A gradient is by of plasma to a density of 12 of a in a B for in a and the a a of is in by enzymatic with is of plasma LDL a of LDL is as the of the of LDL by the of lipoprotein range was as described A. Austin M.A. Brunzell J.D. Hokanson J.E. of LDL particles in normal subjects with LDL A and LDL Thromb. Biol. 1996; Scholar). lipolytic activity was in plasma as described Brunzell J.D. Human lipoprotein lipase: with in to plasma J. Scholar). with and was with plasma for and the were and HL activity, in of of is as the activity in the with a that S.P. Brunzell J.D. and characterization of the of lipoprotein lipase deficiency.Arteriosclerosis. 1989; 9: Scholar, J. Brunzell J.D. Human lipoprotein lipase: of activity, and as with Lipid Res. Scholar). HL was by with human HL A. for of human hepatic 1996; Scholar). and of HL-deficient patients and control subjects presented in TG levels in subjects S-1 and a of more than increase in and LDL cholesterol and apoB was in the HL-deficient patient not All HL-deficient subjects showed a to TG increase across the lipoprotein density spectrum and compared with the control subjects. In HDL cholesterol was in patient than in patients S-1 and S-3 and subjects = in and LDL cholesterol and in a new and LDL particle Subjects = as as to In control subjects as in a new in and LDL cholesterol and as as to In control subjects as HL activity was in the three HL-deficient subjects In S-1 and S-3 had no detectable HL protein in S-2, HL was of the normal for HL in men activity was the HL-deficient patients the were and patients and control subjects. Lipoprotein distribution across a density gradient was by Lipoprotein were as described A. Austin M.A. Brunzell J.D. Hokanson J.E. of LDL particles in normal subjects with LDL A and LDL Thromb. Biol. 1996; Scholar). All three HL-deficient patients had remarkably more buoyant LDL particles as compared with control subjects and In subjects S-1 and with neither HL activity nor HL protein presented with a distinct increase in cholesterol in the IDL and VLDL density range as compared with patient S-2, with detectable HL protein, or the control subjects Lipoprotein was by lipoprotein density range as described (8Zambon A. Austin M.A. Brown B.G. Hokanson J.E. Brunzell J.D. Effect of hepatic lipase on LDL in normal men and those with coronary heart disease.Arterioscler. Thromb. 1993; 13: 147-153Google Scholar, A. Austin M.A. Brunzell J.D. Hokanson J.E. of LDL particles in normal subjects with LDL A and LDL Thromb. Biol. 1996; Scholar). Lipid and apoB in the were the lipid lipoprotein the was for lipid the data the cholesterol distribution subjects S-1 and with no HL activity or HL protein, had a to VLDL concentration, and a to IDL apoB concentration, than subject S-2, with inactive HL protein, or control subjects A increase in the TG content particle was in HL-deficient patients across the apoB-containing lipoprotein density In the HL-deficient the content particle was to the content was to and the content was to compared with control subjects both in vitro and in suggested that HL a role in lipoprotein metabolism independent of its lipolytic activity. This study for the in evidence that HL indeed plays an important role in human lipoprotein metabolism independent of its enzymatic activity. In particular, inactive HL protein appears to affect VLDL and IDL particle HL enzymatic activity seems to influence VLDL-, IDL-, LDL-, and HDL-TG content and their physical The of HL as a lipolytic in lipoprotein metabolism has been for a of two lipase in plasma normal subjects and patients with Scholar, H. A. the of liver Res. 1998; Scholar). the phospholipid and TG content of and HDL HL to their lipid and thereby their density and levels of HL activity to and LDL particles that and (8Zambon A. Austin M.A. Brown B.G. Hokanson J.E. Brunzell J.D. Effect of hepatic lipase on LDL in normal men and those with coronary heart disease.Arterioscler. Thromb. 1993; 13: 147-153Google Scholar). dense LDL with an of disease M.A. J.E. lipoprotein and of 1988; Scholar). A of smaller, and HDL particles has also been with HL activity levels P. Evidence for the role of hepatic endothelial lipase in the metabolism of plasma in Scholar). the the absence of HL activity leads to the of TG lipoproteins, resulting in large buoyant LDL (7Auwerx J. Marzetta C.A. Hokanson J.E. Brunzell J.D. Large buoyant LDL-like particles in hepatic lipase deficiency.Arteriosclerosis. 1989; 9: 319-325Google and HDL particles. The study and by of the in plasma of protein, as in patient S-2, the absence of HL enzymatic activity is with remarkably more buoyant, LDL as compared with the control subjects and (7Auwerx J. Marzetta C.A. Hokanson J.E. Brunzell J.D. Large buoyant LDL-like particles in hepatic lipase deficiency.Arteriosclerosis. 1989; 9: 319-325Google that large LDL particles as their and a of the apoB-containing lipoprotein in HL-deficient in of buoyant LDL particles subject S-1 with human HL in LDL of density and lipid (7Auwerx J. Marzetta C.A. Hokanson J.E. Brunzell J.D. Large buoyant LDL-like particles in hepatic lipase deficiency.Arteriosclerosis. 1989; 9: 319-325Google Scholar). of transgenic overexpressing HL the of in LDL in that HL also VLDL and IDL physical Fan J. M. Taylor J.M. Overexpression of human hepatic lipase and apo in transgenic to cholesterol and lipoprotein Thromb. Biol. Scholar). These a of HL activity on VLDL and IDL lipid study hypothesis by showing that HL enzymatic activity appears to to VLDL-, IDL-, and HDL-TG that HL activity lipoprotein lipid across a lipoprotein density A phospholipid in the VLDL particles was also in HL-deficient no phospholipid in the IDL or LDL particles was The activity of important in the phospholipid lipoproteins, as the phospholipid protein S. Isolation and characterization of a phospholipid protein human Lipid Res. 1988; Scholar), for and to to In addition to its as plasma and both in vitro and in have suggested a role for HL as a ligand that mediates the uptake of lipoproteins lipoprotein by the of lipoproteins with cell surface proteoglycans (9Santamarina-Fojo S. Haudenschild C. Amar M. The role of hepatic lipase in lipoprotein metabolism and atherosclerosis.Curr. Opin. Lipidol. 1998; 9: 211-219Google Scholar, 10Krapp A. Ahle S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP).J. Lipid Res. 1996; 37: 926-936Google Scholar, 11Huff M.W. Miller D.B. Wolfe B.M. Connelly P.W. Sawyez C.G. Uptake of hypertriglyceridmic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.J. Lipid Res. 1997; 38: 1318-1333Google Scholar, 12Ji Z.S. Dichek H.L. Miranda R.D. Mahley R.W. Heparan sulfate proteoglycans participate in hepatic lipase and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins.J. Biol. Chem. 1997; 272: 31285-31292Google Scholar, H.L. Brecht W. Fan J. Ji Z.S. McCormick S.P. Akeefe H. Conzo L. Sanan D.A. Weisgraber K.H. Young S.G. Taylor J.M. Mahley R.W. Overexpression of hepatic lipase in transgenic mice decreases apolipoprotein B-containing and high density lipoproteins. Evidence that hepatic lipase acts as a ligand for lipoprotein uptake.J. Biol. Chem. 1998; Scholar, Amar Haudenschild R.D. R.D. Bensadoun A. J. S. In vivo evidence of both lipolytic and nonlipolytic of hepatic lipase in the metabolism of Thromb. Biol. Scholar). HL appears to increase the binding and uptake of lipoproteins, including and VLDL remnants (9Santamarina-Fojo S. Haudenschild C. Amar M. The role of hepatic lipase in lipoprotein metabolism and atherosclerosis.Curr. Opin. Lipidol. 1998; 9: 211-219Google Scholar, 11Huff M.W. Miller D.B. Wolfe B.M. Connelly P.W. Sawyez C.G. Uptake of hypertriglyceridmic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.J. Lipid Res. 1997; 38: 1318-1333Google Scholar), (10Krapp A. Ahle S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP).J. Lipid Res. 1996; 37: 926-936Google Scholar, 12Ji Z.S. Dichek H.L. Miranda R.D. Mahley R.W. Heparan sulfate proteoglycans participate in hepatic lipase and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins.J. Biol. Chem. 1997; 272: 31285-31292Google Scholar), as as HDL Z.S. Dichek H.L. Miranda R.D. Mahley R.W. Heparan sulfate proteoglycans participate in hepatic lipase and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins.J. Biol. Chem. 1997; 272: 31285-31292Google Scholar), by a of cells in in vivo evidence of a role of HL in lipoprotein metabolism independent of has been by in which a catalytically inactive has been in of both active and catalytically inactive HL in mice the apoB-containing lipoprotein levels by (13Dichek H.L. Brecht W. Fan J. Ji Z.S. McCormick S.P. Akeefe H. Conzo L. Sanan D.A. Weisgraber K.H. Young S.G. Taylor J.M. Mahley R.W. Overexpression of hepatic lipase in transgenic mice decreases apolipoprotein B-containing and high density lipoproteins. Evidence that hepatic lipase acts as a ligand for lipoprotein uptake.J. Biol. Chem. 1998; Scholar), that HL a role in apoB-containing lipoprotein independent of its enzymatic activity. in human subjects. a amount of the HL protein in normal of inactive protein, patient had cholesterol in the VLDL and IDL range as compared with patients S-1 and had neither HL activity nor protein VLDL and IDL apoB concentrations, the of VLDL and IDL were in patients with no protein, patient had IDL and VLDL apoB levels to those in normal control subjects. in the LDL apoB levels was These data that of inactive HL protein affect human VLDL and IDL as in vitro (10Krapp A. Ahle S. Kersting S. Hua Y. Kneser K. Nielsen M. Gliemann J. Beisiegel U. Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP).J. Lipid Res. 1996; 37: 926-936Google Scholar, 11Huff M.W. Miller D.B. Wolfe B.M. Connelly P.W. Sawyez C.G. Uptake of hypertriglyceridmic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.J. Lipid Res. 1997; 38: 1318-1333Google and in (13Dichek H.L. Brecht W. Fan J. Ji Z.S. McCormick S.P. Akeefe H. Conzo L. Sanan D.A. Weisgraber K.H. Young S.G. Taylor J.M. Mahley R.W. Overexpression of hepatic lipase in transgenic mice decreases apolipoprotein B-containing and high density lipoproteins. Evidence that hepatic lipase acts as a ligand for lipoprotein uptake.J. Biol. Chem. 1998; Scholar). LDL appears not to by the of HL protein. In patient S-2, with inactive HL protein, was than in patients S-1 and This with the in lipoprotein metabolism in the of catalytically inactive HL and in of inactive HL had only on HDL levels (13Dichek H.L. Brecht W. Fan J. Ji Z.S. McCormick S.P. Akeefe H. Conzo L. Sanan D.A. Weisgraber K.H. Young S.G. Taylor J.M. Mahley R.W. Overexpression of hepatic lipase in transgenic mice decreases apolipoprotein B-containing and high density lipoproteins. Evidence that hepatic lipase acts as a ligand for lipoprotein uptake.J. Biol. Chem. 1998; or was with a in a of HDL Amar Haudenschild R.D. R.D. Bensadoun A. J. S. In vivo evidence of both lipolytic and nonlipolytic of hepatic lipase in the metabolism of Thromb. Biol. Scholar). The of inactive HL on apoB-containing lipoproteins and HDL metabolism the for in of which to the role of HL in lipoprotein metabolism, independent of its lipolytic activity. In it to the lipid of lipoproteins, and the TG of IDL and their as ligand for Lipoprotein lipase activity was in the HL-deficient patients and control that the of the LDL particles and the TG in lipoprotein as as the of VLDL and IDL particles in S-1 and S-3 were not the of in activity. S-1 and were with a which their activity. These to increase activity by binding and a in the the that K. J. M. Deeb S.S. B. J. and a distinct via a in the lipoprotein lipase J. 1996; Scholar). We with with cholesterol distribution as by or with VLDL and IDL patients with neither HL activity nor HL protein had cholesterol distribution in the VLDL and IDL range as as VLDL and IDL apoB levels of or not In both patient S-1 and were and their cholesterol distribution across the VLDL and IDL density range as as their VLDL and IDL apoB levels were remarkably appears that the in the VLDL and IDL cholesterol distribution and in the of inactive HL protein to with The of lipoprotein TG as as VLDL and IDL for the of by the evidence that three HL-deficient patients had the of and as did of the nine patients with HL deficiency by (1Brunzell J.D. Deeb S.S. Lipoprotein lipase, apo CII and hepatic lipase deficiency.in: Scriver C.R. Beaudet A. Sly W.S. Valle D. Vogelstein B. Childs B. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. McGraw-Hill, New York2000: 2789-2816Google Scholar). The coronary disease that in uptake and of the of apoB-containing lipoproteins of HDL and to participate in cholesterol of the in lipoproteins. A of study the of patients HL deficiency is a with only 12 patients characterized in the (1Brunzell J.D. Deeb S.S. Lipoprotein lipase, apo CII and hepatic lipase deficiency.in: Scriver C.R. Beaudet A. Sly W.S. Valle D. Vogelstein B. Childs B. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. McGraw-Hill, New York2000: 2789-2816Google Scholar). to only three of which has inactive HL protein, the of study evidence both in vitro and in vivo In the study provides in vivo evidence of a role for HL in human lipoprotein metabolism, independent of its lipolytic activity. We that both lipolytic and nonlipolytic of HL important for lipoprotein In particular, HL lipolytic activity lipoprotein lipid across lipoprotein as as LDL density. The of of inactive HL protein remarkably VLDL and VLDL remnant (IDL) plasma The role that both lipolytic and of HL in the and of human to This was by and A of was in the of the of A. is by a the for apolipoprotein coronary artery disease density gradient acid high density lipoprotein HDL cholesterol hepatic lipase intermediate density lipoprotein low density lipoprotein LDL cholesterol lipolytic activity plasma lipoprotein lipase triglyceride very low density