Overexpression of apoC-I in apoE-null mice

Apolipoprotein C-I (apoC22222222246) has been proposed to act primarily via interference with apoE-mediated lipoprotein uptake. To define actions of apoC-I that are independent of apoE, we crossed a moderately overexpressing human apoC-I transgenic, which possesses a minimal phenotype in the WT background, with the apoE-null mouse. Surprisingly, apoE-null/C-I mice showed much more severe hyperlipidemia than apoE-null littermates in both the fasting and non-fasting states, with an almost doubling of cholesterol, primarily in IDL+LDL, and a marked increase in triglycerides; 3-fold in females to 260 ± 80 mg/dl and 14-fold in males to 1409 ± 594 mg/dl. HDL lipids were not significantly altered but HDL were apoC-I-enriched and apoA-II-depleted. Production rates of VLDL triglyceride were unchanged as was the clearance of post-lipolysis remnant particles. Plasma post-heparin hepatic lipase and lipoprotein lipase levels were undiminished as was the in vitro hydrolysis of apoC-I transgenic VLDL. However, HDL from apoC-I transgenic mice had a marked inhibitory effect on hepatic lipase activity, as did purified apoC-I. LPL activity was minimally affected. Atherosclerosis assay revealed significantly increased atherosclerosis in apoE-null/C-I mice assessed via the en face assay.Inhibition of hepatic lipase may be an important mechanism of the decrease in lipoprotein clearance mediated by apoC-I. Apolipoprotein C-I (apoC22222222246) has been proposed to act primarily via interference with apoE-mediated lipoprotein uptake. To define actions of apoC-I that are independent of apoE, we crossed a moderately overexpressing human apoC-I transgenic, which possesses a minimal phenotype in the WT background, with the apoE-null mouse. Surprisingly, apoE-null/C-I mice showed much more severe hyperlipidemia than apoE-null littermates in both the fasting and non-fasting states, with an almost doubling of cholesterol, primarily in IDL+LDL, and a marked increase in triglycerides; 3-fold in females to 260 ± 80 mg/dl and 14-fold in males to 1409 ± 594 mg/dl. HDL lipids were not significantly altered but HDL were apoC-I-enriched and apoA-II-depleted. Production rates of VLDL triglyceride were unchanged as was the clearance of post-lipolysis remnant particles. Plasma post-heparin hepatic lipase and lipoprotein lipase levels were undiminished as was the in vitro hydrolysis of apoC-I transgenic VLDL. However, HDL from apoC-I transgenic mice had a marked inhibitory effect on hepatic lipase activity, as did purified apoC-I. LPL activity was minimally affected. Atherosclerosis assay revealed significantly increased atherosclerosis in apoE-null/C-I mice assessed via the en face assay. Inhibition of hepatic lipase may be an important mechanism of the decrease in lipoprotein clearance mediated by apoC-I. Apolipoprotein C-I (apoC-I), a 6.6 kDa plasma protein that is a component of VLDL, IDL, and HDL, has a variety of metabolic functions that continue to emerge. Early investigations emphasized the effect of apoC-I, along with apoC-II and apoC-III, to displace apoE from triglyceride-rich emulsions and lipoproteins, and to thereby interfere indirectly with lipoprotein clearance (1Windler E. Chao Y. Havel R.J. Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apolipoproteins.J. Biol. Chem. 1980; 255: 8303-8307Google Scholar, 2Quarfordt S.H. Michalopoulos G. Schirmer B. The effect of human C apolipoproteins on the in vitro hepatic metabolism of triglyceride emulsions in the rat.J. Biol. Chem. 1982; 257: 14642-14647Google Scholar). There was also evidence for a direct inhibitory effect of apoC-I on lipoprotein binding to receptors. Either mixed apoCs or purified apoC-I decreased binding of β-VLDL to a remnant receptor, the LDL receptor-related protein (LRP) (3Kowal R.C. Herz J. Weisgraber K.H. Mahley R.W. Brown M.S. Goldstein J.L. Opposing effects of apolipoprotein E and C on lipoprotein binding to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: 10771-10779Google Scholar, 4Weisgraber K.H. Mahley R.W. Kowal R.C. Herz J. Goldstein J.L. Brown M.S. Apolipoprotein C-I modulates the interaction of apolipoprotein E with β-migrating very low density lipoproteins (β-VLDL) and inhibits binding of β-VLDL to low density lipoprotein receptor-related protein.J. Biol. Chem. 1990; 265: 22453-22459Google Scholar), and decreased the apoE-mediated binding of human VLDL and IDL to the LDL receptor (LDLR) (5Windler E.E. Kovanen P.T. Chao Y.S. Brown M.S. Havel R.J. Goldstein J.L. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E.J. Biol. Chem. 1980; 255: 10464-10471Google Scholar, 6Sehayek E. Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.J. Biol. Chem. 1991; 266: 18259-18267Google Scholar). ApoC-I is an activator of lecithin cholesterol acyl transferase (LCAT), though to a lesser extent than apoA-I (7Soutar A.K. Garner C.W. Baker H.N. Sparrow J.T. Jackson R.L. Gotto Jr., A.M. Smith L.C. Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin:cholesterol acyl-transferase.Biochemistry. 1975; 14: 3057-3064Google Scholar, 8Soutar A.K. Sigler G.F. Smith L.C. Gotto Jr., A.M. Sparrow J.T. Lecithin:cholesterol acyltransferase activation and lipid binding by synthetic fragments of apolipoprotein C-I.Scand. J. Clin. Lab. Invest. 1978; 38: 53-58Google Scholar). ApoC-I has been reported to inhibit plasma phospholipase A2 activity (9Poensgen J. Apolipoprotein C-I inhibits the hydrolysis by phospholipase A2 of phospholipids in liposomes and cell membranes.Biochim. Biophys. Acta. 1990; 1042: 188-192Google Scholar). Recently, a previously suggested effect to inhibit cholesteryl ester transfer protein (CETP) (10Kushwaha R.S. Hasan S.Q. McGill Jr., H.C. Getz G.S. Dunham R.G. Kanda P. Characterizations of cholesteryl ester transfer protein inhibitor from plasma of baboons (Papio sp).J. Lipid Res. 1993; 34: 1288-1297Google Scholar) has been exhaustively confirmed (11Gautier T. Masson D. Pais de Barros J.P. Athias A. Gambert P. Aunis D. Metz-Boutigue M.H. Lagrost L. Human apolipoprotein C-I accounts for the ability of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein activity.J. Biol. Chem. 2000; 275: 37504-37509Google Scholar). ApoC-I also was proposed to inhibit lipoprotein lipase (LPL) and hepatic lipase (HL), although the physiological significance of these observations has remained uncertain (12Havel R.J. Fielding C.J. Olivecrona T. Shore V.G. Fielding P.E. Egelrud T. Cofactor activity of protein components of human very low density lipoproteins in the hydrolysis of triglycerides by lipoprotein lipase from different sources.Biochemistry. 1973; 12: 1828-1833Google Scholar, 13Kinnunen P.K.J. Ehnholm C. Effect of serum and c-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase.FEBS Lett. 1976; 65: 354-357Google Scholar). The study of genetically modified mice has made an important contribution to current understanding of the metabolic effects of apoC-I. Elevated triglyceride and cholesterol levels in human apoC-I transgenic mice were first reported by Simonet et al. as part of a study establishing the role of to the in the of apoC-I and apoE the apolipoprotein in transgenic Biol. Chem. 1991; 266: Scholar). et al. an effect of an apoC-I to increase cholesterol and decrease the hepatic uptake of VLDL in transgenic mice A. M.H. and hepatic uptake of VLDL are in transgenic mice human apolipoprotein and human apolipoprotein Biol. Scholar). triglycerides were much in the apoC-I but cholesterol levels were not than levels in transgenic VLDL triglyceride clearance was significantly in transgenic However, was effect of the apoC-I on VLDL clearance in that apoC-I had a in effect on were as decreased remnant uptake by the as the However, the mice also had of from the reported human apoC-I transgenic mice on a WT background, the minimal which we had for apoE and apoC-II Y. A. J.L. Smith of a in the apolipoprotein Lipid Res. 1993; 34: Scholar, T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). ApoC-I transgenic mice had hyperlipidemia with of VLDL and significantly remnant clearance in of the However, the in VLDL clearance was much more severe than the in the uptake of remnant an that remained et al. reported apoC-I transgenic mice that showed a doubling of cholesterol but an increase in However, in was which was to the proposed a transgenic phenotype was in as evidence that inhibition of clearance was part of mechanism M.H. the of the low density lipoprotein receptor, human apolipoprotein C-I in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a pathway.J. Clin. Invest. Scholar). from apoC-I high were to of along with and M.H. and in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). a of apoC-I, to be to metabolism in to decreased that was with increased to also with increased levels is with increased mediated metabolism and in transgenic mice overexpressing human apolipoproteins Scholar). revealed a of increased apoC-I to interfere with lipoprotein clearance via the VLDL receptor G. L. M.H. of in apolipoprotein transgenic mice by of the receptor, but not by the J. Scholar). ApoC-I mice been reported and had an phenotype than an increased to cholesterol that M.H. B. to cholesterol in apolipoprotein J. Scholar). to the of these been as of the of the inhibition by apoC-I of apoE-mediated lipoprotein uptake A had been of However, of transgenic mice in the apoE-null revealed a in role for as an inhibitor of by in part and in part via inhibition of lipoprotein interaction with the T. G. to apolipoprotein in apolipoprotein Apolipoprotein is not mediated by effects on apolipoprotein E.J. Clin. Invest. Scholar). was of in vitro direct inhibition by of both LPL Inhibition of lipoprotein lipase by an of human very low density Biophys. Res. Scholar, R.J. Fielding C.J. Olivecrona T. Shore V.G. Fielding P.E. Egelrud T. Cofactor activity of protein components of human very low density lipoproteins in the hydrolysis of triglycerides by lipoprotein lipase from different sources.Biochemistry. 1973; 12: 1828-1833Google Scholar) and S.H. of apolipoprotein E on and hepatic J. Scholar). to actions of apoC-I that are independent of apoE, we of apoC-I transgenic mice in the confirmed the observations in transgenic mice of inhibition of LPL but revealed a inhibition of that is an important of the role of apoC-I in lipoprotein Human apoC-I transgenic mice for to the were to the mice T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). mice in the were from the Jackson S.H. R.L. and in mice apolipoprotein Scholar, Smith T. A. J.L. and atherosclerosis in apolipoprotein mice by homologous in Scholar). mice were crossed with the mice to mice for the apoE and for the human apoC-I were in an with a to of were a containing of and to and was was in the was were with for via the and for and levels were in fasting and non-fasting plasma from cholesterol, and phospholipids were an from and was the protein assay Human apoC-I were in plasma and lipoproteins of mice an assay modified from a apoE D. J. J. Plasma of apolipoprotein E in lipoproteins in and Biol. Scholar). apoC-I was as the a of in were with the with were with in for with the were for with assay that had been and in with the were for with the the were for with a of in The was to continue for and were ApoC-I were with the of a human plasma of of that had been as P. of apolipoproteins C-I and in human plasma by Chem. Scholar). were for a in The and of for assay were and was on of plasma in were and for cholesterol and triglycerides as of plasma from from were to lipoprotein VLDL and HDL were by density R.J. The and of lipoproteins in human Clin. Invest. 34: Scholar). cholesterol, and protein were on lipoproteins and were by density as L.C. of and and and Scholar, Y. S. H.N. of VLDL apolipoprotein for the of of the of the metabolism of lipoproteins containing apolipoprotein Lipid Res. 1990; Scholar). VLDL, IDL+LDL, and HDL of were by by or The of the on the was confirmed by with the of which was by to primarily apoA-I and were from apoC-I was the of Weisgraber to was the of G. were with to and a VLDL from mice on were as T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). are and cholesterol and a for remnant lipoproteins to apolipoprotein the of the plasma T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). VLDL apolipoproteins were with the an of VLDL was by and to to the of the was mice from were with of the Plasma were and and The in were as the as of the Y. S. H.N. of VLDL apolipoprotein for the of of the of the metabolism of lipoproteins containing apolipoprotein Lipid Res. 1990; Scholar). VLDL triglyceride rates were by the of VLDL by by plasma and as T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). activity was in and post-heparin plasma from mice of an of with C. P.K.J. and of lipoprotein lipase from J. 1975; Scholar). LPL activity was in the plasma in an as Brown of purified hepatic triglyceride lipase and lipoprotein lipase from human postheparin Lipid Res. Scholar, B. Olivecrona T. lipase activity and levels in B Biol. Scholar). VLDL from mice as a or from apoC-I or transgenic mice were as the hydrolysis of VLDL was as D. Apolipoprotein lipid hydrolysis by hepatic Biol. Chem. 2000; 275: Scholar). of VLDL of were with of purified rat A. B. J. of rat hepatic lipase of apolipoprotein E and apolipoprotein Biol. Scholar) in of to a of with were for were by the on levels were the LPL hydrolysis of VLDL was as de A. of very low density lipoproteins by lipoprotein Lipid Res. 38: Scholar). of VLDL triglycerides were for with of purified LPL in with in a of The was by of and the on by of To the effect of HDL on the hydrolysis by and by LPL of a VLDL the assay was of HDL to of HDL different of HDL were HDL from WT mice and from human apoC-I transgenic The effect of human apoC-I on both was assessed by the of to of purified apoC-I to the VLDL of were as mice from were of for the of by the en face the of the D. R.L. to atherosclerosis in mice apolipoprotein or apolipoprotein Clin. Invest. Scholar). The was on a and in the was and the was and with the were and the containing was of in and Biol. Scholar). was by of were to triglyceride levels were for crossed a moderately overexpressing human apoC-I the mice showed much more severe hyperlipidemia than littermates in both the fasting and non-fasting states, with an almost doubling of cholesterol and an increase in the were by males had a 14-fold increase in to with a doubling of cholesterol, females had a 3-fold increase in to with cholesterol levels that almost were in plasma lipids in and by ± ± ± ± ± ± ± ± ± ± ± ± HDL triglycerides; Plasma lipids from females and and females and in a HDL triglycerides; Plasma lipids from females and and females and The of the lipoprotein is in VLDL from mice had an increase in the of lipoprotein a VLDL from mice was triglyceride to The LDL from mice was also increased in and moderately HDL from mice to more to but was not LDL from mice had a significantly ester to cholesterol phospholipids with a for VLDL and of are more with decreased than decreased remnant in and ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± in and Plasma from mice was for lipoprotein the ± for in from in on of not in a in and Plasma from mice was for lipoprotein the ± for in from in on of not of plasma confirmed that mice had increased cholesterol and both in the VLDL and to mice lipoproteins and were by density and in the of showed a increase in the cholesterol and of in The of was also significantly increased in the from which was also significantly to the from although to a lesser extent than the The in mice was on an to the extent and was significantly to the of of VLDL was in the in mice to in of VLDL was in the in mice to in increase in suggested an important effect of apoC-I on not on lipoprotein of density ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± from and the ± for from for in on of in a from and the ± for from for in on of HDL apolipoproteins are to transfer to VLDL in Smith T. A. J.L. and atherosclerosis in apolipoprotein mice by homologous in transfer to be by of apoC-I. of VLDL and from mice showed much more more apoC-I, and apoA-I and than the from mice was confirmed by which in decreased in VLDL HDL from mice had apoA-I but than HDL the was significantly in VLDL from mice but significantly in HDL for apoA-I and in VLDL and HDL from and VLDL. in VLDL and HDL from and To the mechanism the doubling of cholesterol in we the clearance of post-lipolysis lipoproteins from mice There was and mice in the of of these direct effect of apoC-I on post-lipolysis remnant clearance in these To the of increased of VLDL as the mechanism for increased in we the in plasma the of an inhibitor of VLDL in was and mice in the of VLDL as assessed by the increase in plasma the of an effect on VLDL or we the mice for a in clearance of and LPL were in and human apoC-I transgenic mice as post-heparin in in and mice had LPL activity to WT activity was also increased in mice to as we in to increased of the lipase T. G. to apolipoprotein in apolipoprotein Apolipoprotein is not mediated by effects on apolipoprotein E.J. Clin. Invest. Scholar, T. Y. Y. Y. of lipoproteins to decreased in Clin. Invest. 2000; Scholar). the of VLDL as a for both LPL and VLDL from different transgenic and were as for both LPL and not be in these VLDL has very VLDL from mice were by both LPL and with the inhibitory effect of on both LPL and (12Havel R.J. Fielding C.J. Olivecrona T. Shore V.G. Fielding P.E. Egelrud T. Cofactor activity of protein components of human very low density lipoproteins in the hydrolysis of triglycerides by lipoprotein lipase from different sources.Biochemistry. 1973; 12: 1828-1833Google Scholar, Inhibition of lipoprotein lipase by an of human very low density Biophys. Res. Scholar, S.H. of apolipoprotein E on and hepatic J. Scholar). There was in the hydrolysis by of VLDL from To a more physiological in which apolipoproteins from HDL an important role activation of lipoprotein by apolipoprotein Biol. Chem. 1990; 265: Scholar), we the assay in the of HDL from or WT HDL from mice had apoA-I and to that from WT to increased apoC-I The in the HDL, as was in the HDL, but was not HDL from WT or mice had effect on the hydrolysis of WT VLDL by LPL HDL VLDL hydrolysis by in a HDL from mice was a much inhibitor of hydrolysis of VLDL by VLDL from mice were with of HDL from mice or apoC-I transgenic mice by by the with the of purified apoC-I in of HDL to apolipoprotein be for the inhibitory effect of The of apoC-I to the VLDL hydrolysis in a inhibition of LPL activity that was high and of apoC-I in a inhibition of hydrolysis that was and that activity The VLDL and HDL from mice had of and mg/dl of human apoC-I, for of VLDL and of HDL of the proposed effect of on atherosclerosis in the a atherosclerosis assay was to the effect on atherosclerosis of the with the apoC-I C. G. lipase plasma cholesterol but to atherosclerosis in apolipoprotein Biol. Chem. Scholar). revealed significantly more atherosclerosis in mice ± of ± for with the increase in that we in these the study we the effects of apoC-I in the of apoE in the of effects to apoC-I and mice had increased VLDL and to an increase in and a doubling of very high levels of There was a in the effect on as is with metabolic in mice B. The as a for human and Scholar). The were reported with apoC-I transgenic in the background, a very phenotype T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar). The for of lipids to be the inhibition of that was proposed by an in vitro study P.K.J. Ehnholm C. Effect of serum and c-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase.FEBS Lett. 1976; 65: 354-357Google Scholar) and that is in in transgenic decreased clearance of VLDL of to the remnant clearance and evidence for decreased by LPL A. M.H. and hepatic uptake of VLDL are in transgenic mice human apolipoprotein and human apolipoprotein Biol. Scholar, T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar, M.H. the of the low density lipoprotein receptor, human apolipoprotein C-I in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a pathway.J. Clin. Invest. Scholar). There was evidence in the current study for as effects on VLDL on the of in the of the lipoproteins, was inhibitory effect on the phospholipase activity of the effect of apoC-I as a phospholipase A2 inhibitor (9Poensgen J. Apolipoprotein C-I inhibits the hydrolysis by phospholipase A2 of phospholipids in liposomes and cell membranes.Biochim. Biophys. Acta. 1990; 1042: 188-192Google Scholar). that been by phospholipase are and may not be to the J. of by the rat J. 1980; Scholar, J. Plasma clearance and uptake of by hepatic lipase evidence for a and apolipoprotein pathway.J. Lipid Res. Scholar). However, effect on post-lipolysis remnant clearance was were effects on or levels with the moderately in study not A effect of the to increase plasma significance in the fasting in both males and a is with increased mediated metabolism and in transgenic mice overexpressing human apolipoproteins Scholar). the effect on was mediated by HDL and by apoC-I but not by VLDL, to in the or of the apoC-I in VLDL, protein is a much of inhibition of both LPL and was with VLDL, with the and different for the inhibition mediated by these ApoC-I in HDL was more than purified apoC-I as an to the of purified apolipoproteins and be to very different A. of the protein component of serum high density Biophys. Acta. 1975; Scholar). the inhibition of LPL by apoC-I that was also in the not to be (12Havel R.J. Fielding C.J. Olivecrona T. Shore V.G. Fielding P.E. Egelrud T. Cofactor activity of protein components of human very low density lipoproteins in the hydrolysis of triglycerides by lipoprotein lipase from different sources.Biochemistry. 1973; 12: 1828-1833Google Scholar, A. M.H. and hepatic uptake of VLDL are in transgenic mice human apolipoprotein and human apolipoprotein Biol. Scholar, T. G. J.L. H.N. Smith hyperlipidemia in transgenic mice overexpressing human apolipoprotein Clin. Invest. Scholar, M.H. the of the low density lipoprotein receptor, human apolipoprotein C-I in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a pathway.J. Clin. Invest. Scholar). The effects of transgenic HDL and purified apoC-I on as to LPL that apoC-I was the To of the mice were and genetically than the or of the on of the effects of the on HDL as an an inhibitor of decreased along with an increase in the S. C. E. J.L. A. Human inhibits the hydrolysis of HDL triglyceride and the decrease of HDL by and cholesteryl ester transfer protein in transgenic Clin. Invest. Scholar, E. G. D. C. S. J. of human apolipoprotein in mice to very low density lipoprotein Biol. Chem. Scholar, S. J. L. A. J.L. HDL levels in part by inhibition of hepatic in and hepatic lipase Lipid Res. Scholar, The of apolipoproteins on the hepatic hydrolysis of high density lipoprotein and Biol. Chem. Scholar, of and hepatic lipase to HDL and Lipid Res. Scholar). with increased has been to the clearance of A. Jr., J. Jr., S. evidence for both and of hepatic lipase in the metabolism of Biol. 2000; Scholar). activity of hepatic lipase also be to increase the of apoA-I in HDL which to the increase in the in vitro that hepatic lipase the of apolipoprotein in Biophys. Acta. 1990; Scholar). The phenotype not the phenotype of a genetically in the increased plasma were C. G. lipase plasma cholesterol but to atherosclerosis in apolipoprotein Biol. Chem. Scholar). However, human to decreased or of an is with hyperlipidemia with a component that is to the in apoC-I transgenic mice P. A. G. G. with a of hepatic 1982; Scholar, J. L. P. in of hepatic lipase is with and in and in of with Biol. 2000; Scholar, from and metabolic Scholar). The of protein in the human a than a clearance by the of cholesteryl ester uptake and as has been in mice with a for an A. Jr., J. Jr., S. evidence for both and of hepatic lipase in the metabolism of Biol. 2000; Scholar). the the the of a the high levels of LPL that are in the to hepatic and of but not as the of the of de J. S.H. J. in mice of the hepatic lipase Biol. Chem. Scholar). apoC-I is as an inhibitor in the may be a that is to in the hepatic and role not be for by of by in or a phenotype to that in A. of apolipoprotein in the LDL density in inhibition of hepatic Biophys. Acta. Scholar, H.N. Brown metabolism inhibition of hepatic triglyceride lipase in the Clin. Invest. 1982; Scholar). The also decreased the of The in the lipoprotein of these may the for atherosclerosis in mice was to an increase in the low levels of HDL that are in mice C. G. lipase plasma cholesterol but to atherosclerosis in apolipoprotein Biol. Chem. Scholar). increase in HDL was in with the reported in to increased had a minimal effect on HDL J. L. Weisgraber K.H. Mahley R.W. of hepatic lipase in transgenic mice apolipoprotein and high density that hepatic lipase as a for lipoprotein Biol. Chem. Scholar). are also with atherosclerosis assay in to a decrease in atherosclerosis R.L. Jackson R.L. Human hepatic triglyceride lipase high density lipoprotein and cholesterol in transgenic Biol. Chem. Scholar). The extent of contribution of of apoC-I to the physiological effect of apoC-I in the of apoE However, on we that the effect of apoC-I to interfere with apoE-mediated lipoprotein remnant clearance may be in to interference with actions of that to the apoE-mediated clearance S. J. of and hepatic by a cell in Biophys. Acta. Scholar, S. A. Mahley R.W. binding and uptake of remnant lipoproteins by hepatic in Biol. Chem. Scholar, Mahley R.W. in hepatic lipase and apolipoprotein binding and uptake of plasma lipoproteins, high density Biol. Chem. Scholar, E. of the LDL receptor, the LDL and hepatic lipase in remnant by the Lipid Res. Scholar, S. C. of hepatic and lipoprotein lipase in lipoprotein metabolism and in transgenic and and J. 2000; Scholar, lipoproteins and Scholar). was by and by a from the to for apolipoprotein apoE cholesterol human apoC-I transgenic for the and for the human apoC-I HDL cholesterol hepatic lipase LDL receptor LDL receptor-related protein

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