Phosphatidylinositol promotes cholesterol transport and excretion

Administration of phosphatidylinositol (PI) to New Zealand white rabbits increases HDL negative charge and stimulates reverse cholesterol transport. Intravenously administered PI (10 mg/kg) associated almost exclusively with the HDL fraction in rabbits. PI promoted an increase in the hepatic uptake of plasma free cholesterol (FC) and a 21-fold increase in the biliary secretion of plasma-derived cholesterol. PI also increased cholesterol excretion into the feces by 2.5-fold. PI directly affects cellular cholesterol metabolism. In cholesterol-loaded macrophages, PI stimulated cholesterol mass efflux to lipid-poor reconstituted HDL. PI was about half as effective as cAMP at stimulating efflux, and the effects of cAMP and PI were additive. In cultured HepG2 cells, PI-enriched HDL also enhanced FC uptake from HDL by 3-fold and decreased cellular cholesterol synthesis and esterification. PI enrichment had no effect on the selective uptake of cholesterol esters or on the internalization of HDL particles. PI-dependent metabolic events were efficiently blocked by inhibitors of protein kinase C and the inositol signaling cascade.The data suggest that HDL-PI acts via cell surface ATP binding cassette transporters and signaling pathways to regulate both cellular and intravascular cholesterol homeostasis. Administration of phosphatidylinositol (PI) to New Zealand white rabbits increases HDL negative charge and stimulates reverse cholesterol transport. Intravenously administered PI (10 mg/kg) associated almost exclusively with the HDL fraction in rabbits. PI promoted an increase in the hepatic uptake of plasma free cholesterol (FC) and a 21-fold increase in the biliary secretion of plasma-derived cholesterol. PI also increased cholesterol excretion into the feces by 2.5-fold. PI directly affects cellular cholesterol metabolism. In cholesterol-loaded macrophages, PI stimulated cholesterol mass efflux to lipid-poor reconstituted HDL. PI was about half as effective as cAMP at stimulating efflux, and the effects of cAMP and PI were additive. In cultured HepG2 cells, PI-enriched HDL also enhanced FC uptake from HDL by 3-fold and decreased cellular cholesterol synthesis and esterification. PI enrichment had no effect on the selective uptake of cholesterol esters or on the internalization of HDL particles. PI-dependent metabolic events were efficiently blocked by inhibitors of protein kinase C and the inositol signaling cascade. The data suggest that HDL-PI acts via cell surface ATP binding cassette transporters and signaling pathways to regulate both cellular and intravascular cholesterol homeostasis. It has been known for over 30 years that the altered lipoprotein metabolism in many dyslipidemic states is associated with abnormally charged lipoprotein particles (1Noble R.P. Electrophoretic separation of plasma lipoproteins in agarose gel.J. Lipid Res. 1968; 9: 693-700Google Scholar). There is now accumulating evidence that this abnormal charge may directly contribute to aberrant lipoprotein metabolism (2Ghosh S. Basu M.K. Schweppe J.S. Charge heterogeneity of human low density lipoprotein (LDL).Proc. Soc. Exp. Biol. Med. 1973; 142: 1322-1325Google Scholar, 3La Belle M. Blanche P.J. Krauss R.M. Charge properties of low density lipoprotein subclasses.J. Lipid Res. 1997; 38: 690-700Google Scholar, 4Mishra V.K. Palgunachari M.N. Datta G. Phillips M.C. Lund-Katz S. Adeyeye S.O. Segrest J.P. Anantharamaiah G.M. Studies of synthetic peptides of human apolipoprotein A-I containing tandem amphipathic a-helixes.Biochemistry. 1998; 37: 10313-10324Google Scholar, 5Lund-Katz S. Laplaud P.M. Phillips M.C. Chapman M.J. Apolipoprotein B-100 conformation and particle surface charge in human LDL subspecies: implication for LDL receptor interaction.Biochemistry. 1998; 37: 12867-12874Google Scholar). Lipoproteins all exhibit a net negative charge, and this charge is determined by both the apolipoprotein and lipid constituents of the lipoprotein particle (6Sparks D.L. Lund-Katz S. Phillips M.C. The charge and structural stability of apolipoprotein A-I in discoidal and spherical recombinant high density lipoprotein particles.J. Biol. Chem. 1992; 267: 25839-25847Google Scholar, 7Davidson W.S. Sparks D.L. Lund-Katz S. Phillips M.C. The molecular basis for the difference in charge between pre-beta- and alpha-migrating high density lipoproteins.J. Biol. Chem. 1994; 269: 8959-8965Google Scholar, 8Chauhan V. Wang X. Ramsamy T. Milne R.W. Sparks D.L. Evidence for lipid-dependent structural changes in specific domains of apolipoprotein B100.Biochemistry. 1998; 37: 3735-3742Google Scholar). The primary anionic lipid in lipoprotein particles is phosphatidylinositol (PI). While PI is a minor constituent (3–7%) of lipoprotein phospholipids (7Davidson W.S. Sparks D.L. Lund-Katz S. Phillips M.C. The molecular basis for the difference in charge between pre-beta- and alpha-migrating high density lipoproteins.J. Biol. Chem. 1994; 269: 8959-8965Google Scholar, 9Kuksis A. Myher J.J. Geher K. Breckenridge W.C. Jones G.J. Little J.A. Lipid class and molecular species interrelationships among plasma lipoproteins of normolipemic subjects.J. Chromatogr. 1981; 224: 1-23Google Scholar), studies suggest that it may be a critical component of chyle and an important regulator of lipoprotein secretion (10Chu S.W. Geyer R.P. myo-Inositol action on gerbil intestine. Association of phosphatidylinositol metabolism with lipid clearance.Biochim. Biophys. Acta. 1982; 710: 63-70Google Scholar, 11Holub B.J. Metabolism and function of myo-inositol and inositol phospholipids.Annu. Rev. Nutr. 1986; 6: 563-597Google Scholar). Our work has shown that HDL charge directly affects lipid metabolism by controlling interactions with interfacial enzymes (12Sparks D.L. Pritchard P.H. Transfer of cholesteryl ester into high density lipoprotein by cholesteryl ester transfer protein: effect of HDL lipid and apoprotein content.J. Lipid Res. 1989; 30: 1491-1498Google Scholar, 13Sparks D.L. Frank P.G. Neville T.A. Effect of the surface lipid composition of reconstituted LPA-I on apolipoprotein A-I structure and lecithin: cholesterol acyltransferase activity.Biochim. Biophys. Acta. 1998; 1390: 160-172Google Scholar, 14Sparks D.L. Frank P.G. Braschi S. Neville T.A. Marcel Y.L. Effect of apolipoprotein A-I lipidation on the formation and function of pre-beta and alpha-migrating LpA-I particles.Biochemistry. 1999; 38: 1727-1735Google Scholar, 15Coffill C.R. Ramsamy T.A. Hutt D.M. Schultz J.R. Sparks D.L. Diacylglycerol is the preferred substrate in high density lipoproteins for human hepatic lipase.J. Lipid Res. 1997; 38: 2224-2231Google Scholar) and cell surface molecules (16Zhao Y. Sparks D.L. Marcel Y.L. Effect of the apolipoprotein A-I and surface lipid composition of reconstituted discoidal HDL on cholesterol efflux from cultured fibroblasts.Biochemistry. 1996; 35: 16510-16518Google Scholar, 17Zhao Y. Sparks D.L. Marcel Y.L. Specific phospholipid association with apolipoprotein A-I stimulates cholesterol efflux from human fibroblasts. Studies with reconstituted sonicated lipoproteins.J. Biol. Chem. 1996; 271: 25145-25151Google Scholar). It is now clear that PI affects lipoprotein metabolism both by controlling interfacial interactions and uniquely regulating intracellular signaling pathways. We have previously reported that a single intravenous injection of PI liposomes into fasted rabbits increases the net negative surface charge of HDL and almost completely inhibits lecithin:cholesterol acyltransferase (LCAT) (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). PI therefore directly acts to block the synthesis and storage of cholesteryl ester in the blood stream. In addition, PI appeared to stimulate reverse cholesterol transport (RCT) by promoting a 30-fold increase in the rate of clearance of free cholesterol (FC) from the circulation (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). Previous work has shown that infusion of lecithin liposomes can also promote cholesterol transport; however, the doses utilized to obtain the effect were about 30-fold greater than that required with PI (19Friedman M. Byers S.O. Rosenman R.H. Resolution of aortic atherosclerotic infiltration in the rabbit by phosphatidate infusion.Proc. Soc. Exp. Biol. Med. 1957; 95: 586-588Google Scholar, 20Rodrigueza W.V. Klimuk S.K. Pritchard P.H. Hope M.J. Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles.Biochim. Biophys. Acta. 1998; 1368: 306-320Google Scholar, 21Rodrigueza W.V. Mazany K.D. Essenburg A.D. Pape M.E. Rea T.J. Bisgaier C.L. Williams K.J. Large versus small unilamellar vesicles mediate reverse cholesterol transport in vivo into two distinct hepatic metabolic pools. Implications for the treatment of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2132-2139Google Scholar, 22Williams K.J. Werth V.P. Wolff J.A. Intravenously administered lecithin liposomes: a synthetic antiatherogenic lipid particle.Perspect. Biol. Med. 1984; 27: 417-431Google Scholar). Large unilamellar lecithin vesicles (∼120 nm) appear to promote a rapid mobilization of tissue cholesterol with consequent increases in plasma cholesterol levels (20Rodrigueza W.V. Klimuk S.K. Pritchard P.H. Hope M.J. Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles.Biochim. Biophys. Acta. 1998; 1368: 306-320Google Scholar). The liver then acts to clear the cholesterol-enriched vesicles, and it is thought that the antiatherogenic propensity of this infusate results from their ability to act as of from the to the liver (20Rodrigueza W.V. Klimuk S.K. Pritchard P.H. Hope M.J. Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles.Biochim. Biophys. Acta. 1998; 1368: 306-320Google Scholar, 21Rodrigueza W.V. Mazany K.D. Essenburg A.D. Pape M.E. Rea T.J. Bisgaier C.L. Williams K.J. Large versus small unilamellar vesicles mediate reverse cholesterol transport in vivo into two distinct hepatic metabolic pools. Implications for the treatment of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2132-2139Google Scholar). of induced has been reported in intravenous of lecithin liposomes (19Friedman M. Byers S.O. Rosenman R.H. Resolution of aortic atherosclerotic infiltration in the rabbit by phosphatidate infusion.Proc. Soc. Exp. Biol. Med. 1957; 95: 586-588Google Scholar, 20Rodrigueza W.V. Klimuk S.K. Pritchard P.H. Hope M.J. Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles.Biochim. Biophys. Acta. 1998; 1368: 306-320Google Scholar, 21Rodrigueza W.V. Mazany K.D. Essenburg A.D. Pape M.E. Rea T.J. Bisgaier C.L. Williams K.J. Large versus small unilamellar vesicles mediate reverse cholesterol transport in vivo into two distinct hepatic metabolic pools. Implications for the treatment of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2132-2139Google Scholar, 22Williams K.J. Werth V.P. Wolff J.A. Intravenously administered lecithin liposomes: a synthetic antiatherogenic lipid particle.Perspect. Biol. Med. 1984; 27: 417-431Google Scholar). The that PI also stimulates and results in a net of cholesterol from the In this have the ability of PI to directly in and have the of action of PI in and HepG2 We that a single intravenous injection of PI almost with HDL particles and promotes a increase in the of cholesterol from the plasma to the The of action of PI to both transporters and cellular signaling pathways. was from and liver PI were from was from and were from was from and were from receptor class were from were from or and was from or HepG2 were from the Lipoproteins were from the plasma of or from rabbit plasma by as by R.W. and of apolipoprotein 1986; Scholar). and PI vesicles in were by as previously (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). the lipoprotein was for at with or PI vesicles HDL the was on a (10 HDL and in the in HDL surface charge was determined by on agarose apolipoprotein A-I was by to was in and and HDL particles were by of a of Specific of in were was and the was sonicated with a for at at for 30 and sonicated for at was and the was sonicated for at with between The particles were then the plasma clearance of of vesicles containing of or of PI vesicles containing of was via the into fasted New Zealand white rabbits The were were and of plasma was for lipoprotein at of was to the density to density was to a The was to at for to a LDL and fraction and an HDL The of phospholipids in the lipoprotein was then determined by The effects of phospholipid on cholesterol in liver and were determined as rabbits were via the with of PI or vesicles containing the were and at a injection to blood The was and the and were The liver was then in and was from the associated with was by in were determined on the and of rapid of lipid and 37: Scholar). The effects of phospholipids on cholesterol and levels were determined in were with of PI or vesicles, and feces were for were and the were in by the of of Acta. Scholar), and cholesterol and were in were and into Frank P.G. V. M. E. Marcel Y.L. of the of apolipoprotein A-I cell surface binding and lipid efflux in 1999; 38: Scholar), and cholesterol efflux from the was determined as previously S. Marcel Y.L. and of the apolipoprotein A-I and in cholesterol Biol. Chem. Scholar). HepG2 were cultured in with containing and were into and to for HepG2 were with and then in the containing of or and HDL as inhibitors of and protein kinase C or were at this and at in The were at and at the were to on The were then with and then with The was with and the were on a The cell were for and for protein by the effects of inhibitors on cholesterol with HepG2 cell were at with containing or PI-enriched HDL. were in the at the the were on and then in The data as a of the difference between uptake and with data the and of at in a with HepG2 cell were at with containing or PI-enriched HDL. were in the at the the were on and then in The data as a of the difference between uptake and with data the and of at HepG2 were to in The were with and then at with containing and HDL that was in or PI as the were on the and the cell with and with The were then with for at of the cell was to the and rapid of lipid and 37: Scholar) and by on a of The of the containing cholesterol and cholesterol ester were into and was determined by We have previously reported that intravenous of the anionic into rabbits promoted changes in plasma cholesterol metabolism and an of cholesterol from the plasma (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). the of administered PI in PI was administered and blood were at for the of HDL and by density of plasma that greater than of the with the of a and that the PI as a lipid and was over the the clearance of PI and from the circulation as a function of PI is than and is by In about of the of at and at of the plasma lipoproteins that associated almost exclusively with the HDL fraction at and is in with studies that increased PI mass in HDL by (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). HDL PI was and levels by with HDL at at and with the lipoprotein was from the circulation to with a of were associated with the and LDL the and were from the circulation with a the enhanced cholesterol clearance effects of PI be the of increased hepatic uptake and biliary of rabbits were with vesicles containing and then with a injection containing of PI or 30 the were and liver and and for the of 30 and of the had in the of and The of cholesterol in liver and is shown in In liver was a increase in cholesterol in with of a 21-fold increase in cholesterol in versus In a HDL was PI-enriched and in and then administered to rabbits. In this an increase in biliary with and enhanced biliary may cholesterol and levels were determined at for a single injection of or PI injection increased cholesterol and at a increase over with cholesterol levels on over and to levels by In of or in cholesterol over the of or had no effect on the of Our that PI a enhanced cholesterol clearance from the the of cholesterol in the plasma over a (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). that PI may stimulate a an enhanced mobilization or efflux of cholesterol into the blood and a clearance of cholesterol from this HDL-PI directly affects cholesterol efflux the effect of PI on cholesterol efflux from cholesterol-loaded HDL particles in cholesterol were utilized to cholesterol and were to of two molecules of and an of PI or were then with cholesterol-loaded macrophages, and the efflux of cholesterol from the was with or with that PI stimulated cholesterol efflux in a to that shown for to a The lipid was about half as effective as the the effect on cholesterol efflux was also cAMP and appeared greater in than in the of PI-dependent cellular effects were shown to be completely blocked by inhibitors and PI may uptake and transport pathways in the also the effect of PI on the uptake of HDL cholesterol and cholesterol ester by hepatic cell In the effect of PI on the transfer of or ester into HepG2 that PI-enriched HDL cholesterol to HepG2 than HDL. had no effect on cholesterol uptake from LDL or The enrichment of HDL with PI also had no effect on the uptake of cholesteryl ester by HepG2 with HDL may suggest that the human of is in cholesterol In with this PI-dependent cholesterol uptake in HepG2 was by of an that inhibits both and uptake In addition, PI was also to stimulate cholesterol uptake from HDL to in We also the effect of PI enrichment on the cell association of HDL PI enrichment of HDL in a small of about in the cell association of HDL at all that the increased cholesterol uptake in to PI enrichment was the of particle internalization and metabolism. cholesterol uptake from HDL was by the of an of PI-dependent and an of into the In a reported C the We also inhibitors of the inositol and protein kinase and kinase and cholesterol uptake in to PI by and The protein kinase C blocked cholesterol cholesterol uptake was shown to be to the as by the a The inositol signaling is reported to intracellular metabolism the of from the also that promotes of also cholesterol as the and The results suggest that the cholesterol metabolic effects of PI the of specific and inositol in intracellular the ability of PI to promote the excretion of cholesterol in rabbits may also be to an of cholesterol synthesis or the effects of PI on cholesterol synthetic pathways in HepG2 In studies the of into cholesterol or cholesterol ester was determined in the or of PI-enriched HDL. of of HDL in the a increase in the of into cholesterol with with In with PI-enriched HDL levels of cholesterol of the ester a increase in cholesterol with the of was blocked with enrichment of HDL with PI the that lipoprotein metabolism and can be by the of the anionic We previously reported that intravenous of PI into rabbits a increase in the net negative surface charge of the plasma lipoproteins (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). We now that administered PI almost exclusively with the HDL fraction and is from the circulation than is in to studies that that PI may be than (10Chu S.W. Geyer R.P. myo-Inositol action on gerbil intestine. Association of phosphatidylinositol metabolism with lipid clearance.Biochim. Biophys. Acta. 1982; 710: 63-70Google Scholar). also no evidence of in the plasma with this and that PI is in the blood is cell studies that PI on intracellular signaling pathways. PI two in HDL that of a surface charge and that of a of the vesicles of the anionic phospholipid PI into rabbits also a increase in the clearance of FC from plasma and that PI may be stimulating (18Stamler C.J. Breznan D. Neville T.A. Viau F.J. Camlioglu E. Sparks D.L. Phosphatidylinositol promotes cholesterol transport in vivo. [In Process Citation].J. Lipid Res. 2000; 41: 1214-1221Google Scholar). has been in the of PI promoted an increase in the hepatic uptake of plasma cholesterol and a increase in the biliary secretion of the plasma-derived cholesterol. Evidence that this excretion is stimulated by a PI-enriched HDL have shown that the of the PI with the HDL and directly affects the enzymes (LCAT) and cell surface events that regulate the metabolism of HDL cholesterol. injection of PI-enriched HDL was shown to promote a increase in hepatic uptake and biliary secretion of to that with injection of PI studies that PI is to stimulate cholesterol uptake from and from LDL or with that have shown that HDL cholesterol is the primary of biliary cholesterol of free cholesterol from lipoproteins for biliary cholesterol secretion in Scholar). PI to stimulate to a that of cholesterol from the in the is to that of M. T.A. of excretion infusion of recombinant reverse cholesterol transport in 1999; Scholar). of liposomes into also promoted a net cholesterol excretion from the M. T.A. of excretion infusion of recombinant reverse cholesterol transport in 1999; however, the of the increase stimulated by the infusate was than that in this PI the HDL in this may suggest that PI the cholesterol and transport of the HDL may of as work has shown that stimulating with of HDL into atherosclerotic rabbits can directly regression of aortic and lipid J.J. V. of atherosclerotic by high density lipoprotein plasma fraction in the cholesterol-fed Scholar). is thought to both an efflux in cholesterol is from cell by and a clearance in the is and in the The of HDL in promoting cholesterol efflux is now and thought to be to the of the and the M. E. P.G. G. cholesterol Scholar). PI enrichment of reconstituted HDL stimulates the efflux of cholesterol from cholesterol-loaded of with cAMP has been previously shown to of and stimulate cholesterol efflux S.W. Williams D.L. Phillips M.C. of cellular cholesterol efflux to apolipoprotein A-I by Biophys. Acta. 1999; Scholar). In the that PI also increases cholesterol efflux and that this effect is with cAMP In have that of an of promoted a of cholesterol uptake into HepG2 cells, that PI may act by the or of the PI also increased cholesterol efflux particles or were as cholesterol however, efflux were almost that shown for the reconstituted HDL is also with and that efflux is to the of phospholipid in particles M. G. of the cholesterol efflux properties of human by enrichment with Lipid Res. 1997; 38: Scholar, V. of HDL phospholipid in efflux of cell cholesterol to studies with human Lipid Res. 1996; 37: Scholar, W.S. W.V. Lund-Katz S. Phillips M.C. of particle on the efflux of cellular free Biol. Chem. Scholar). results suggest that PI the of and the with appear to this Previous by have changes in the intracellular metabolism of inositol in to the of PI C.R. of phosphatidylinositol by liposomes containing Scholar, C.R. Phosphatidylinositol liposomes by stimulate phosphatidylinositol in Biophys. Res. 1986; Scholar). with results in suggest that HDL-PI is by a to the and inositol of the inositol may from an increased of intracellular PI and increased substrate for the of In this cholesterol uptake was almost by an of C J.J. P.H. and of C in 1998; Scholar, C.R. C.J. The C increases in by and 1998; Scholar, J.R. M. G. M. G. M. of C by in in cholesterol 2000; Scholar), was by a C S. Y. of C in of protein kinase in 2000; Scholar, P.H. C increases in Biophys. Acta. 2000; Scholar). Cholesterol uptake was also shown to be stimulated by and PI-dependent cholesterol uptake was by a and inhibitors of inositol kinase M. G. S. G. signaling by Res. Scholar, C.J. The of phosphatidylinositol by and Biophys. Res. 1992; Scholar, M. K. K. M. Y. T. inhibits and phosphatidylinositol kinase by in cultured aortic Scholar, A. is a phosphatidylinositol the of phosphatidylinositol in Scholar, J.A. P.G. Schultz R.M. C.J. Studies on the of phosphatidylinositol by and Med. Chem. 1996; Scholar), and and function in treatment of Scholar, M. of as an of 1998; Scholar, X. D. Y. of and in human plasma mass Chromatogr. Scholar, D. M. as 1981; all efficiently cholesterol uptake in to that PI promotes inositol signaling and by in intracellular It has also been reported previously that the of PI liposomes to the of increases uptake into A. S. A. Phosphatidylinositol liposomes increase uptake and tissue secretion by human Med. Biol. Scholar). In to effect on cholesterol uptake by cells, also directly the synthesis of cholesterol in HepG2 In with the of the of HDL to cultured promoted an increase in cholesterol synthesis Effect of plasma lipoproteins and on the of of Biophys. Acta. Scholar, of in liver cell Biol. Chem. however, this effect of HDL was by the enrichment of HDL with mobilization from the has been reported to promote the of S. S. of in the of Biol. Chem. Scholar, that in the mobilization and of into the rapid of that is by 269: Scholar, in the of protein to of rate of synthesis mobilization in of to the Scholar, The of protein and of in the effects of mobilization on in Scholar), and therefore PI may cholesterol synthesis in by intracellular increased cholesterol into the directly the of at a A. G. M. G. S. is by cholesterol and by in Med. 2000; Scholar, and of hepatic the of cholesterol Soc. Exp. Biol. Med. 2000; 224: Scholar, A. J.A. of with 1999; Scholar). PI-enriched HDL also decreased the intracellular this effect is the of a of in or the of decreased cholesterol synthesis is In studies that the of the anionic lipid PI promotes effects on both intravascular cholesterol storage and PI inhibits cholesteryl ester by and storage in the blood stream. PI stimulates an that results in the net excretion of cholesterol from the it that the of can cholesterol is in the blood or from the The of PI from studies with cultured cells, to both the efflux and the clearance of cholesterol from HDL particles that and signaling and in cellular acts a of lipoprotein charge and cell signaling pathways to both and cellular cholesterol homeostasis. with free cholesterol phosphatidylinositol reverse cholesterol transport

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