Modulation of hepatic lipoprotein synthesis and secretion by taxifolin, a plant flavonoid

In the present study, the effects of taxifolin, a plant flavonoid, on lipid, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) synthesis and secretion were determined in HepG2 cells. Pretreatment of cells with (±)-taxifolin led to an inhibition of cholesterol synthesis in a dose- and time-dependent manner, with an 86 ± 3% inhibition at 200 μM observed within 24 h. As to the mechanism underlying this inhibitory effect, taxifolin was shown to inhibit the activity of HMG-CoA reductase by 47 ± 7%. In addition, cellular cholesterol esterification, and triacylglycerol and phospholipid syntheses, were also significantly suppressed in the presence of taxifolin. ApoA-I and apoB synthesis and secretion were then studied by pulse-chase experiments. ApoA-I secretion was found to increase by 36 ± 10%. In contrast, an average reduction of 61 ± 8% in labeled apoB in the medium was apparent with taxifolin. This effect on secretion appeared not to be exerted at the transcriptional level. Rather, the effect on apoB secretion was found to be exerted in the early stages of apoB degradation and to be sensitive to dithiothreitol (DTT) and insensitive to N-acetylleucyl-leucyl-norleucinal, suggesting a proteolytic pathway involving a DTT-sensitive protease. Fractionation of secreted apoB revealed a slight shift in the distribution of secreted apoB-containing lipoproteins. Cholesteryl ester, rather than triacylglycerol, was shown to be the lipid that primarily regulated apoB secretion. In summary, our data suggest that taxifolin decreases hepatic lipid synthesis with a concomitant decrease and increase in apoB and apoA-I secretion, respectively.—Theriault, A., Q. Wang, S. C. Van Iderstine, B. Chen, A. A. Franke, and K. Adeli. Modulation of hepatic lipoprotein synthesis and secretion by taxifolin, a plant flavonoid. J. Lipid Res. 2000. 41: 1969–1979. In the present study, the effects of taxifolin, a plant flavonoid, on lipid, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) synthesis and secretion were determined in HepG2 cells. Pretreatment of cells with (±)-taxifolin led to an inhibition of cholesterol synthesis in a dose- and time-dependent manner, with an 86 ± 3% inhibition at 200 μM observed within 24 h. As to the mechanism underlying this inhibitory effect, taxifolin was shown to inhibit the activity of HMG-CoA reductase by 47 ± 7%. In addition, cellular cholesterol esterification, and triacylglycerol and phospholipid syntheses, were also significantly suppressed in the presence of taxifolin. ApoA-I and apoB synthesis and secretion were then studied by pulse-chase experiments. ApoA-I secretion was found to increase by 36 ± 10%. In contrast, an average reduction of 61 ± 8% in labeled apoB in the medium was apparent with taxifolin. This effect on secretion appeared not to be exerted at the transcriptional level. Rather, the effect on apoB secretion was found to be exerted in the early stages of apoB degradation and to be sensitive to dithiothreitol (DTT) and insensitive to N-acetylleucyl-leucyl-norleucinal, suggesting a proteolytic pathway involving a DTT-sensitive protease. Fractionation of secreted apoB revealed a slight shift in the distribution of secreted apoB-containing lipoproteins. Cholesteryl ester, rather than triacylglycerol, was shown to be the lipid that primarily regulated apoB secretion. In summary, our data suggest that taxifolin decreases hepatic lipid synthesis with a concomitant decrease and increase in apoB and apoA-I secretion, respectively.—Theriault, A., Q. Wang, S. C. Van Iderstine, B. Chen, A. A. Franke, and K. Adeli. Modulation of hepatic lipoprotein synthesis and secretion by taxifolin, a plant flavonoid. J. Lipid Res. 2000. 41: 1969–1979. There has been a considerable amount of interest in the benefits of diets rich in flavonoid-containing foods, such as fruits, vegetables, wine, and tea, with respect to cardiovascular disease (CVD) and certain cancers (1Hollman P.C. Hertgo M.G. Katan M.B. Role of dietary flavonoids in protection against cancer and coronary heart disease.Biochem. Soc. Trans. 1996; 24: 785-789Google Scholar). The protective effects of flavonoids against these chronic diseases have been attributed to their free radical-scavenging property. In the case of CVD, flavonoids have been shown to reduce low density lipoprotein (LDL) oxidation, an important step in atherogenesis (2De Whalley C.V. Rankin S.M. Hoult J.R. Jessup W. Leake D.S. Flavonoids inhibit the antioxidative modification of low density lipoproteins.Biochem. Pharmacol. 1990; 39: 1743-1749Google Scholar, 3Hayek T. Fuhrman B. Vaya J. Rosenblat M. Belinky P. Coleman R. Elis A. Aviram M. Reduced progression of atherosclerosis in apoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2744-2752Google Scholar). However, studies have given evidence about the potential role of these flavonoids in reducing blood lipid levels. Investigations by Choi, Yokozawa, and Oura (4Choi J.S. Yokozawa T. Oura H. Antihyperlipidemic effects of flavonoids from Prunus Davidiana.J. Nat. Prod. 1991; 54: 218-224Google Scholar) and Jahromi and Ray (5Jahromi M.A.F. Ray A.B. Antihyperlipidemic effect of flavonoids from Pterocarpus marsupium.J. Nat. Prod. 1993; 56: 989-994Google Scholar) showed that flavonoid components of Prunus davidiana stem extract and Pterocarpus marsupium heartwood extract reduced cholesterol levels in hyperlipidemic rats. In humans, the intake of soy protein rich in isoflavonoids was shown to significantly reduce serum cholesterol levels (6Anderson J.W. Johnstone B.M. Cook-Newll M.E. Meta-analysis of the effects of soy protein intake on serum lipids.N. Engl. J. Med. 1995; 333: 276-282Google Scholar). In elucidating the molecular mechanism of flavonoid action on cholesterol homeostasis, at least two enzymes involved in cholesterol metabolism were shown to be involved. Work by Wilcox et al. (7Wilcox L.J. Borradaile N.M. Kurowska E.M. Telford D.E. Huff M.W. Naringenin, a citrus flavonoid, markedly decreases apoB secretion in HepG2 cells and inhibits acyl CoA: cholesterol acyltransferase.Circulation. 1998; 98 (Abstract): I-537Google Scholar) and Borradaile, Carroll, and Kurowska (8Borradaile N.M. Carroll K.K. Kurowska E.M. Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin.Lipids. 1999; 34: 591-598Google Scholar) provided evidence that the citrus flavonoids naringenin and hesperetin decreased cholesterol synthesis by inhibiting acyl-CoA:cholesterol acyltransferase (ACAT) activity in HepG2 cells. In contrast, Nassuato et al. (9Nassuato G. Iemmolo R.M. Strazzabosco M. Lirussi F. Deana R. Francesconi M.A. Muraca M. Passera D. Fragasso A. Orlando R. Csomos G. Okolicsanyi L. Effect of silibinin on biliary lipid composition: experimental and clinical study.J. Hepatol. 1991; 12: 290-295Google Scholar) demonstrated in rat liver that silybin, the major flavolignan from the fruit of Silybum marianum (syn. Carduus marianus L.), reduced cholesterol synthesis by suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, the rate-limiting enzyme in cholesterol synthesis. Bok et al. (10Bok S-H. Lee S-H. Park Y-B. Bae K-H. Son K-H. Jeong T-S. Choi M-S. Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl-glutaryl-CoA reductase and acyl CoA:cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids.J. Nutr. 1999; 129: 1182-1185Scopus (317) Google Scholar) showed in vivo that a combination of these two lipogenic enzymes may account for the hypocholesterolemic effect of flavonoids. Despite these findings, it is unclear whether all naturally derived flavonoids (well over 4,000 of them) share these properties. Moreover, whether all flavonoid molecules function to the same degree in cholesterol synthesis remains to be addressed. The effect of silybin on cholesterol metabolism was further studied in hypercholesterolemic subjects (9Nassuato G. Iemmolo R.M. Strazzabosco M. Lirussi F. Deana R. Francesconi M.A. Muraca M. Passera D. Fragasso A. Orlando R. Csomos G. Okolicsanyi L. Effect of silibinin on biliary lipid composition: experimental and clinical study.J. Hepatol. 1991; 12: 290-295Google Scholar). Although biliary cholesterol concentrations were found to be reduced, the exact compound(s) for this effect was et al. D. J. inhibits the of in Med. 1998; Scholar) studied in rats the hypocholesterolemic effects of a mixture of from S. and silybin, a found that silybin was not as as suggesting that of in to silybin, may also have hypocholesterolemic the of taxifolin, has the of our taxifolin the flavonoid in the flavolignan silybin the of our was to the effects of taxifolin on apolipoprotein (apoB), and apolipoprotein A-I (apoA-I) synthesis and secretion, a as the from was in and at for than the was in medium to a of The was by HepG2 cells were from serum and were from and were from were from A and were from apoB was from cells were from were from The and the were from were from HepG2 cell were in medium with at with and and in about was cells were with taxifolin in cells taxifolin. the of cholesterol and synthesis and secretion, and cells were labeled with for h. and on the were labeled with for h. the medium was and the cells were with and medium were then with as by and J. S. M. of in Scholar). The was and were in and on a and were a were in and then in The were and the were with and to the lipid were in and on a lipid cell were in of and as activity was in HepG2 cells to and degradation of A reductase in Biol. Scholar). and in were with as by et al. A. Q. A. K. of on apolipoprotein B and secretion in HepG2 Thromb. Vasc. Biol. 1999; Scholar). cells were with and for the The cells were in dithiothreitol and ± taxifolin for at The enzyme was by and ± taxifolin for at the was by the of and further for at to The from was by a to that the was with of the was in and an was on a was by in and with The to the was in a and on a were and to the from cells. was to the for cholesterol was determined to the by and J. S. M. of in Scholar). with or taxifolin for to serum and for a further in the presence and of taxifolin. The of to was The cells were then with the were in and was by as protein was determined as was to the to for and HepG2 cells were in for and with an medium at in ± for the the cells were with and in with ± taxifolin. were and cells were in as A. Q. A. K. of on apolipoprotein B and secretion in HepG2 Thromb. Vasc. Biol. 1999; Scholar). The were for in a and the were for at were as to cell and with a and μM to and as A. Q. A. K. of on apolipoprotein B and secretion in HepG2 Thromb. Vasc. Biol. 1999; Scholar). and apoA-I levels were by an as by and A protection with to levels of and in cell Lipid Res. 1990; Scholar). This was by the labeled with cellular in of at apoB or apoA-I was by the of A and in for at was then with and of for on was and with was by the in a for apoB was provided by of apoA-I was from the were to a as the to A was to to the was for as an were and to pulse-chase as The medium was the to and by as A. Q. A. K. of on apolipoprotein B and secretion in HepG2 Thromb. Vasc. Biol. 1999; Scholar). was at at for in an were and the density and apoB were in the as protein was to M. A and sensitive for the of of protein the of Scholar) as the The activity of the medium was the to the were to the amount of cellular were with a with the of at studies were to an of taxifolin that inhibit cholesterol synthesis cell As shown in taxifolin in concentrations to the medium for 24 decreased the of of cellular cholesterol in a inhibition was ± at ± at and 86 ± 3% at 200 or 200 was of the effect not from cells with 200 μM taxifolin that the flavonoid not cellular protein synthesis not this was in the following experiments. 200 the decrease in cellular cholesterol was by a decrease in free cholesterol and ± and ± of studies of HepG2 cells with 200 μM taxifolin were also In these cells were and labeled with a medium with and taxifolin for a of and 24 h. The inhibitory effect of taxifolin on cholesterol synthesis was found to be with an inhibition observed within 24 not In all further a was of cholesterol the medium was also in cells with and 200 μM taxifolin. showed a to that observed significantly the secretion of free cholesterol and by ± and ± the data suggest that the inhibition of cholesterol synthesis in a concomitant decrease in its secretion in the underlying mechanism of action of taxifolin on cholesterol activity was by the of of in cells. This has been and has been to that activity degradation of A reductase in Biol. Scholar, Modulation of reductase by Biol. 1993; Scholar). the the and As shown in taxifolin 24 reduced activity by 47 ± This suggest that taxifolin its effect the inhibition of the rate-limiting enzyme in cholesterol further the effect of taxifolin on cholesterol was determined in by the of of cellular As shown in taxifolin 24 reduced cholesterol by ± suggesting that taxifolin may also However, the that the decreased activity observed may have led to a decrease in cholesterol to lower levels of further the effects of taxifolin on the synthesis and secretion of and HepG2 cells were labeled with with and 200 μM taxifolin for a of 24 h. As in taxifolin showed an inhibitory effect on the of ± and ± in the inhibitory effects on the secretion of ± with a inhibition of phospholipid secretion ± were also observed with their synthesis level. A pulse-chase was to the of apoB and apoA-I in and cell were with for and with medium ± taxifolin for to or of the and were at and A showed a and in of apoA-I and not is a the amount of apoB and secreted by HepG2 cells in the presence and of taxifolin in a pulse-chase in two in A decrease in the of apoB was apparent with taxifolin at the the was further a reduction in the labeled apoB was with a increase in secreted labeled In the presence of taxifolin, a reduction in apoB secretion was with the cells at the This effect on secretion with taxifolin was to that of that the reduction in apoB secretion may be to a decrease in a transcriptional of taxifolin on the synthesis and secretion of and a or HepG2 cells were and as in The was at the of the the was at the of the The were to of and the data on and synthesis and secretion to as ± of in In the amount of apoA-I secreted in the presence and of taxifolin was also a increase in apoA-I secretion in cells was observed with A increase was for its synthesis in two in The increase in apoA-I secretion that the inhibitory effect of taxifolin on apoB secretion is and that taxifolin may have benefits to density lipoprotein As the of synthesis and secretion were also the from in are in of was by and A increase in the synthesis of ± was observed at the of the The increase in synthesis to an increase in secretion ± at the of the This further that the inhibitory effect of taxifolin on apoB secretion is The increase in and apoA-I is and may a transcriptional This is with the mechanism of action of silybin, a flavolignan a taxifolin activity P. Silybum marianum 1995; Scholar). that the effect on apoB and apoA-I secretion appeared to be exerted at the synthesis of these whether their may be a sensitive was to apoB and apoA-I levels. our μM taxifolin, 24 hepatic apoB and apoA-I with the cells This transcriptional effects and that are and apoA-I in and and apoA-I levels are as of of the ± of in the ± of two in ± ± ± ± and apoA-I levels are as of of the ± of in the ± of two in in a the distribution of secreted apoB-containing lipoprotein with taxifolin, the density of secreted in HepG2 cells was by secreted by cells was observed to have a density to that of as has been observed in studies in A. J. The and secretion of apolipoprotein 1999; As in taxifolin markedly reduced the amount of secreted with a slight shift in the density of secreted This that taxifolin and lipid synthesis the secretion of taxifolin the of further degradation of apoB has been as the major mechanism of action in secretion A. J. The and secretion of apolipoprotein 1999; Scholar, L. pathway degradation of apolipoprotein 1996; Scholar). whether is involved in the in apoB secretion, pulse-chase were and cells were for with and and taxifolin. a the cells were for and for apoB As shown in of to the cells and to apoB a degradation of In the presence of taxifolin and apoB cellular was further reduced and was not by This that may be for apoB and F. T. triacylglycerol protein degradation of apolipoprotein A is J. 1996; Scholar) have that a DTT-sensitive may be involved in the early stages of apoB the that such a the effect of taxifolin on apoB secretion. a as by and Role of in the and secretion of apolipoprotein Lipid Res. 1996; Scholar). and cells were for with and in the presence and of taxifolin. a the cells were for and for apoB as shown in of to the cells and apoB cellular to the cells and Despite a reduction in protein synthesis with as has been observed by F. T. triacylglycerol protein degradation of apolipoprotein A is J. 1996; Scholar, Role of in the and secretion of apolipoprotein Lipid Res. 1996; the effect of taxifolin on early apoB degradation was This suggest that a DTT-sensitive may be involved. the effect of taxifolin on apoB secretion μM to and in were in the presence or of taxifolin and B the amount of apoB secreted over a in the presence and of taxifolin. with were in the presence of medium medium medium and medium with showed a of apoB secretion with cells. with and taxifolin in a lower of apoB secretion decrease in also in a of apoB secretion with the cells In contrast, the effect of with taxifolin was than with as taxifolin was shown to markedly the effect of on apoB secretion in is a plant flavonoid in the fruit of S. This also as has been as a plant for the of liver diseases in and in P. Silybum marianum 1995; The as a mixture of with components such as taxifolin. of to silybin, a that taxifolin be studied as a potential hypocholesterolemic The present evidence that taxifolin is of lipid and apolipoprotein studies the effects of taxifolin on lipid synthesis and secretion in HepG2 cells. that taxifolin is to decrease cholesterol in a dose- and time-dependent was by as as at 200 a at cell was not this was in the following and a this taxifolin was shown to inhibit free cholesterol and synthesis. Moreover, and phospholipid synthesis was also found to be significantly with on with that from silybin and by Nassuato et al. (9Nassuato G. Iemmolo R.M. Strazzabosco M. Lirussi F. Deana R. Francesconi M.A. Muraca M. Passera D. Fragasso A. Orlando R. Csomos G. Okolicsanyi L. Effect of silibinin on biliary lipid composition: experimental and clinical study.J. Hepatol. 1991; 12: 290-295Google et al. F. G. G. The effect of silybin on liver phospholipid synthesis in the rat in and et al. A. M. L. Effect of the of on serum lipid Scholar) showed that silybin and decreased hepatic synthesis of and the our are in with the citrus flavonoids hesperetin and were shown to have inhibitory effect in a effect on free and phospholipid synthesis in HepG2 cells (7Wilcox L.J. Borradaile N.M. Kurowska E.M. Telford D.E. Huff M.W. Naringenin, a citrus flavonoid, markedly decreases apoB secretion in HepG2 cells and inhibits acyl CoA: cholesterol acyltransferase.Circulation. 1998; 98 (Abstract): I-537Google Scholar, N.M. Carroll K.K. Kurowska E.M. Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin.Lipids. 1999; 34: 591-598Google Scholar). The in may stem from in the flavonoid taxifolin to be than hesperetin and naringenin in reducing lipid synthesis. is that taxifolin may have a transcriptional in with such as the of the medium was also in cells. a decrease in free and with a inhibition of phospholipid secretion with the effect observed on phospholipid synthesis. In elucidating the mechanism of action on cholesterol the effect of taxifolin on activity, a enzyme in cholesterol Nassuato et al. (9Nassuato G. Iemmolo R.M. Strazzabosco M. Lirussi F. Deana R. Francesconi M.A. Muraca M. Passera D. Fragasso A. Orlando R. Csomos G. Okolicsanyi L. Effect of silibinin on biliary lipid composition: experimental and clinical study.J. Hepatol. 1991; 12: 290-295Google Scholar) demonstrated a inhibition of by showed that the taxifolin of silybin also Although the at taxifolin may be its effect on the data about the at taxifolin hepatic lipid synthesis. taxifolin is to a these taxifolin may be and J. A. J. Csomos G. cell protection in liver Scholar, C. and activity of plant D. in Scholar). that flavonoids may also inhibit activity and cholesterol has been by a of studies (7Wilcox L.J. Borradaile N.M. Kurowska E.M. Telford D.E. Huff M.W. Naringenin, a citrus flavonoid, markedly decreases apoB secretion in HepG2 cells and inhibits acyl CoA: cholesterol acyltransferase.Circulation. 1998; 98 (Abstract): I-537Google Scholar, S-H. Lee S-H. Park Y-B. Bae K-H. Son K-H. Jeong T-S. Choi M-S. Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl-glutaryl-CoA reductase and acyl CoA:cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids.J. Nutr. 1999; 129: 1182-1185Scopus (317) Google Scholar, H. T. K. effects of and its components on cholesterol synthesis in HepG2 evidence from the HepG2 cells and in of Med. 1997; Scholar, L.J. Borradaile Huff M.W. The soy and decrease apolipoprotein B secretion by HepG2 1999; (Abstract): Scholar). whether taxifolin this property. have shown that taxifolin reduced the of cellular in suggesting activity may also be involved. However, as in activity the decreased activity may have led to the decreased cholesterol to the lower levels of an important role in cholesterol our by the effects of taxifolin on apoA-I and apoB synthesis and secretion. Although apoA-I is associated with and is involved in the cholesterol apoB is associated with LDL and is to be it cholesterol to the pulse-chase the of synthesis and secretion were found the of to be markedly decreased in cellular apoB and in cellular suggesting that in the of apolipoprotein synthesis may be involved. The in the amount of cellular apoA-I and apoB in the presence of taxifolin a effect on apoA-I and apoB levels in the synthesis was found to be the that taxifolin of apoB and apoA-I was not However, in the case of these of action are have that in apoB secretion are primarily regulated and degradation in A. J. The and secretion of apolipoprotein 1999; to this apoB associated with the of the is by the L. pathway degradation of apolipoprotein 1996; apoB is to be by an K. J. A. M. R. D. B is associated with an in HepG2 Biol. 1997; Scholar) or to the for degradation W. L. degradation of apolipoprotein B and apolipoprotein B the Biol. 1998; Scholar). In addition, is that a DTT-sensitive may be involved in the early stages of apoB degradation F. T. triacylglycerol protein degradation of apolipoprotein A is J. 1996; Scholar, M. H. A for apoB degradation in HepG2 Biol. 1997; Scholar). are with early degradation by a decrease in the of apoB at the of the in our pulse-chase experiments. Although the apoB was found to evidence of was provided by our our data the that taxifolin is involved at an early of apoB and that the effect of taxifolin on apoB secretion. In contrast, the of to the against of the in in apoB secretion. the mechanism of lipoprotein with apoB to a degradation are with and F. T. triacylglycerol protein degradation of apolipoprotein A is J. 1996; protein was shown to a proteolytic this is with the from Borradaile, Carroll, and Kurowska (8Borradaile N.M. Carroll K.K. Kurowska E.M. Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin.Lipids. 1999; 34: 591-598Google Scholar) on the inhibitory effects of naringenin and hesperetin on apoB secretion. As observed by these with the to increase apoB secretion, that degradation was not involved. The exact and role of our DTT-sensitive in apoB degradation to be The of reduced apoB secretion of cells with taxifolin is also by the of the lipoprotein showed a reduced of labeled apoB in the medium of cells with taxifolin. major shift in the distribution of secreted was observed with cells. these that taxifolin decreased the of secreted a major in the density of the lipoproteins. The effect on apoB synthesis and secretion was found to be with apoA-I and and apoA-I synthesis and secretion were shown to be This effect is and may a transcriptional This is with the mechanism of action of silybin, the flavolignan a taxifolin activity to be important in the of liver P. Silybum marianum 1995; Scholar). However, the apoA-I with taxifolin, suggesting that may be involved. silybin, as as were shown in hypercholesterolemic rats to increase levels D. J. inhibits the of in Med. 1998; is with our on taxifolin to have benefits to The of is a that the synthesis and of and lipid is a major in the and secretion of studied the effects of on the of taxifolin to reduce apoB secretion in HepG2 cells. The of and has been shown to the secretion of apoB in these cells S. secretion of apolipoprotein from HepG2 cells by inhibiting early degradation of apolipoprotein Biol. 1991; Scholar, The effect of low density and on apolipoprotein B in HepG2 Biol. Scholar). to of these showed a increase in apoB secretion in and cells. of taxifolin with a reduction in apoB secretion was the effects were with markedly the secretion of The that taxifolin the effect of lipid is and may that rather than is primarily associated with in apoB secretion taxifolin taxifolin may be its action by for the of In summary, the data in this that taxifolin the synthesis and secretion of a of in to apoB and apoA-I secretion. This the that taxifolin, the of the flavolignan silybin, may a important of This may also account for the hypocholesterolemic activity of to The activity of taxifolin may to an with hypocholesterolemic and properties. The was by a of from the for of acyl-CoA:cholesterol acyltransferase apolipoprotein A-I apolipoprotein apoB-containing lipoprotein serum cardiovascular disease dithiothreitol density lipoprotein 3-hydroxy-3-methylglutaryl-coenzyme A reductase low density lipoprotein triacylglycerol

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