The magnitude of decrease in hepatic very low density lipoprotein apolipoprotein B secretion is determined by the extent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition in miniature pigs.

It has been postulated that the rate of hepatic very low density lipoprotein (VLDL) apolipoprotein (apo) B secretion is dependent upon the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. To test this hypothesis in vivo, apoB kinetic studies were carried out in miniature pigs before and after 21 days treatment with high-dose (10 mg/kg/day), atorvastatin (A) or simvastatin (S) (n = 5). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/day; 0.1%). Statin treatment decreased plasma total cholesterol [31 (A) vs. 20% (S)] and low density lipoprotein (LDL) cholesterol concentrations [42 (A) vs. 24% (S)]. Significant reductions in plasma total triglyceride (46%) and VLDL triglyceride (50%) concentrations were only observed with (A). Autologous [131I]VLDL, [125I]LDL, and [3H]leucine were injected simultaneously, and apoB kinetic parameters were determined by triple-isotope multicompartmental analysis using SAAM II. Statin treatment decreased the VLDL apoB pool size [49 (A) vs. 24% (S)] and the hepatic VLDL apoB secretion rate [50 (A) vs. 33% (S)], with no change in the fractional catabolic rate (FCR). LDL apoB pool size decreased [39 (A) vs. 26% (S)], due to reductions in both the total LDL apoB production rate [30 (A) vs. 21% (S)] and LDL direct synthesis [32 (A) vs. 23% (S)]. A significant increase in the LDL apoB FCR (15%) was only seen with (A). Neither plasma VLDL nor LDL lipoprotein compositions were significantly altered. Hepatic HMG-CoA reductase was inhibited to a greater extent with (A), when compared with (S), as evidenced by 1) a greater induction in hepatic mRNA abundances for HMG-CoA reductase (105%) and the LDL receptor (40%) (both P < 0.05); and 2) a greater decrease in hepatic free (9%) and esterified cholesterol (25%) (both P < 0.05). We conclude that both (A) and (S) decrease hepatic VLDL apoB secretion, in vivo, but that the magnitude is determined by the extent of HMG-CoA reductase inhibition.

Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs.

An orally bioavailable acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, avasimibe (CI-1011), was used to test the hypothesis that inhibition of cholesterol esterification, in vivo, would reduce hepatic very low density (VLDL) apolipoprotein (apo) B secretion into plasma. ApoB kinetic studies were carried out in 10 control miniature pigs, and in 10 animals treated with avasimibe (10 mg/kg/d, n = 6; 25 mg/kg/d, n = 4). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/d; 0.1%). Avasimibe decreased the plasma concentrations of total triglyceride, VLDL triglyceride, and VLDL cholesterol by 31;-40% 39-48%, and 31;-35%, respectively. Significant reductions in plasma total cholesterol (35%) and low density lipoprotein (LDL) cholesterol (51%) concentrations were observed only with high dose avasimibe. Autologous 131I-labeled VLDL, 125I-labeled LDL, and [3H]leucine were injected simultaneously into each pig and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). Avasimibe decreased the VLDL apoB pool size by 40;-43% and the hepatic secretion rate of VLDL apoB by 38;-41%, but did not alter its fractional catabolism. Avasimibe decreased the LDL apoB pool size by 13;-57%, largely due to a dose-dependent 25;-63% in the LDL apoB production rate. Hepatic LDL receptor mRNA abundances were unchanged, consistent with a marginal decrease in LDL apoB FCRs. Hepatic ACAT activity was decreased by 51% (P = 0.050) and 68% (P = 0.087) by low and high dose avasimibe, respectively. The decrease in total apoB secretion correlated with the decrease in hepatic ACAT activity (r = 0.495; P = 0.026). We conclude that inhibition of hepatic ACAT by avasimibe reduces both plasma VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion.

The HMG-CoA reductase inhibitor atorvastatin increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs.

We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (apoB) secretion into plasma. To test the hypothesis that atorvastatin modulates exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given to 6 control miniature pigs and to 6 animals after 28 days of treatment with atorvastatin 3 mg. kg-1. d-1. A multicompartmental model was developed by use of SAAM II and kinetic analysis performed on the plasma retinyl palmitate (RP) data. Peak TRL (d<1.006 g/mL; Sf>20) triglyceride concentrations were decreased 29% by atorvastatin, and the time to achieve this peak was delayed (5.2 versus 2.3 hours; P<0.01). The TRL triglyceride 0- to 12-hour area under the curve was decreased by 24%. In contrast, atorvastatin treatment had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma; however, the TRL RP 0- to 12-hour area under the curve was decreased by 20%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate was increased significantly, 1.4-fold (3.093 versus 2.276 pools/h; P=0.012), with atorvastatin treatment. The percent conversion of TRL RP from the rapid-turnover to the slow-turnover compartment was decreased by 47% with atorvastatin treatment. The TRL RP fractional clearance rate was negatively correlated with very low density lipoprotein apoB production rate measured in the fasting state (r=-0.49). Thus, although atorvastatin had no effect on intestinal TRL assembly and secretion, plasma TRL clearance was significantly increased, an effect that may relate to a decreased competition for removal processes by hepatic very low density lipoprotein.

Inhibition of cholesterol esterification by DuP 128 decreases hepatic apolipoprotein B secretion in vivo: effect of dietary fat and cholesterol.

To further test the hypothesis that newly synthesized cholesteryl esters regulate hepatic apolipoprotein B (apoB) secretion into plasma, apoB kinetic studies were carried out in seven control miniature pigs and in seven animals after 21 days intravenous administration of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor DuP 128 (2.2 mg/kg/day). Pigs were fed a fat (34% of calories; polyunsaturated/monounsaturated/saturated ratio, 1:1:1) and cholesterol (400 mg/day; 0.1%; 0.2 mg/kcal) containing pig chow based diet. DuP 128 significantly reduced total plasma triglyceride and very low density lipoprotein (VLDL) triglyceride concentrations by 36 and 31%, respectively (P<0.05). Autologous 131I-VLDL and 125I-LDL were injected simultaneously into each pig and apoB kinetic data was analyzed using multicompartmental analysis (SAAM II). The VLDL apoB pool size decreased by 26% (0.443 vs. 0.599 mg/kg; P<0. 001) which was due entirely to a 28% reduction in VLDL apoB production or secretion rate (1.831 vs. 2.548 mg/kg/h; P=0.006). The fractional catabolic rate (FCR) for VLDL apoB was unchanged. The LDL apoB pool size and production rate were unaffected by DuP 128 treatment. Hepatic microsomal ACAT activity decreased by 51% (0.44 vs. 0.90 nmol/min/mg; P<0.001). Although an increase in hepatic free cholesterol and subsequent decrease in both LDL receptor expression and LDL apoB FCR might be expected, this did not occur. The concentration of hepatic free cholesterol decreased 12% (P=0.008) and the LDL apoB FCR were unaffected by DuP 128 treatment. In addition, DuP 128 treatment did not alter the concentration of hepatic triglyceride or the activity of diacylglycerol acyltransferase, indicating a lack of effect of DuP 128 on hepatic triglyceride metabolism. In our previous studies, DuP 128 treatment of miniature pigs fed a low fat, cholesterol free diet, decreased VLDL apoB secretion by 65% resulting in a reduction in plasma apoB of 60%. We conclude that in miniature pigs fed a high fat, cholesterol containing diet, the inhibition of hepatic cholesteryl ester synthesis by DuP 128 decreases apoB secretion into plasma, but the effect is attenuated relative to a low fat, cholesterol free diet.

Inhibition of HMG-CoA reductase by atorvastatin decreases both VLDL and LDL apolipoprotein B production in miniature pigs.

In the present studies, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin was used to test the hypothesis that inhibition of cholesterol biosynthesis in vivo with a consequent reduction in the availability of hepatic cholesterol for lipoprotein synthesis, would (1) reduce very low density lipoprotein (VLDL) apolipoprotein B (apoB) secretion into the plasma, (2) reduce the conversion of VLDL apoB to LDL apoB, and (3) reduce LDL apoB direct synthesis. ApoB kinetic studies were carried out in six control miniature pigs and in six animals after 21 days of administration of atorvastatin (3 mg/kg per day). Pigs were fed a fat- (34% of calories; polyunsaturated to monounsaturated to saturated ratio, 1:1:1) and cholesterol- (400 mg/d cholesterol; 0.1%; 0.2 mg/kcal) containing pig chow-based diet. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL cholesterol, total triglyceride, and VLDL triglyceride concentrations by 16%, 31%, 19%, and 28%, respectively (P < .01). Autologous 131I-VLDL, 125I-LDL, and [3H]leucine were injected simultaneously into each pig, and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). The VLDL apoB pool size decreased by 29% (0.46 versus 0.65 mg/kg; P = .002), which was entirely due to a 34% reduction in the VLDL apoB production rate (PR) (1.43 versus 2.19 mg/kg per hour; P = .027). The fractional catabolic rate (FCR) was unchanged. The LDL apoB pool size decreased by 30% (4.74 versus 6.75 mg/kg; P = .0004), which was due to a 22% reduction in the LDL apoB PR (0.236 versus 0.301 mg/kg per hour; P = .004), since the FCR was unchanged. The reduction in LDL apoB PR was primarily due to a 34% decrease in conversion of VLDL apoB to LDL apoB; however, this reduction was not statistically significant (P = .114). Hepatic apoB mRNA abundance quantitated by RNase protection assay was decreased by 13% in the atorvastatin-treated animals (P = .003). Hepatic and intestinal LDL receptor mRNA abundances were not affected. We conclude that inhibition of hepatic HMG-CoA reductase by atorvastatin reduces both VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion into the plasma and not by an increase in hepatic LDL receptor expression. This decrease in apoB secretion may, in part, be due to a reduction in apoB mRNA abundance.

Inhibition of hepatic ACAT decreases ApoB secretion in miniature pigs fed a cholesterol-free diet.

To test the hypothesis that hepatic cholesteryl ester is involved in the regulation of apolipoprotein (apo) B secretion into plasma, apoB kinetic studies were performed in six control miniature pigs and in six pigs after a 21-day administration of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor DuP 128 (2.2 mg.kg-1.d-1 i.v.). Pigs were fed low-fat, cholesterol-free diets. Total plasma cholesterol, triglyceride, very-low-density lipoprotein (VLDL) triglyceride, and low-density lipoprotein (LDL) cholesterol decreased 18%, 29%, 40%, and 26% respectively (P < .03). 131I-VLDL and 125I-LDL were injected simultaneously into each animal, and apoB kinetics were analyzed by using multi-compartmental analysis (SAAM30). VLDL apoB pool size decreased significantly by 60% (0.32 versus 0.84 mg/kg), which was due to a 65% reduction in the VLDL apoB production or secretion rate (1.03 versus 2.94 mg.kg-1.h-1). The fractional catabolic rate was unchanged. LDL apoB pool size decreased nonsignificantly by 18% (5.61 versus 6.90 mg/kg) due entirely to a 24% decrease in production rate (0.26 versus 0.34 mg.kg-1.h-1). At necropsy, hepatic microsomal ACAT activity decreased by 68% (0.28 versus 0.88 nmol.min-1.mg-1; P < .0002). Although an increase in hepatic free cholesterol leading to a decreased LDL receptor expression might be expected, this did not occur. The concentration of hepatic cholesterol and the LDL apoB fractional catabolic rate were unaffected by DuP 128. In addition, the concentration of hepatic triglyceride and the activity of diacylglycerol acyltransferase were not altered by DuP 128, indicating a lack of effect of DuP 128 on hepatic triglyceride metabolism. We conclude that inhibition of hepatic cholesteryl ester synthesis in vivo decreases apoB secretion into plasma.

Lipoprotein lipases, lipoprotein density gradient profile and LDL receptor activity in miniature pigs fed fish oil and corn oil.

The effects of fish oil and corn oil on plasma lipoprotein concentrations, the lipolytic enzymes, lipoprotein lipase and hepatic triacylglycerol lipase, the density distribution of the plasma lipoproteins and LDL receptor activity were studied. These experiments were designed, in part, to define the mechanism(s) responsible for the increased conversion of plasma VLDL apolipoprotein B to LDL and a decreased LDL apolipoprotein B fractional catabolic rate described in previous apolipoprotein B kinetic studies. Miniature pigs were fed diets for 3 to 6 weeks containing supplements of corn oil or fish oil as Maxepa. Triacylglycerol and cholesterol in plasma and VLDL were significantly reduced by the fish oil diet. LDL and HDL cholesterol were not significantly changed. The fish oil diet significantly reduced post-heparin plasma lipoprotein lipase and hepatic triacylglycerol lipase activities, which may be an adaptive response to the low concentration of substrates (triacylglycerol-rich lipoproteins) for these enzymes. No differences were observed in the density of VLDL, LDL or HDL as determined by density gradient ultracentrifugation with the fish oil diet. No major changes in percent lipid composition of VLDL, LDL and HDL were observed. No differences were found with respect to LDL uptake by J774 macrophages. Receptor mediated clearance of LDL in vivo, as assessed by measuring the difference in fractional catabolic rate of native vs. methylated LDL decreased significantly by 17% (P < 0.032). We conclude that the increased conversion of VLDL apolipoprotein B to LDL in miniature pigs fed fish oil is not related to an increase in lipolytic enzymes or density distribution of VLDL, but may be due in part to a decrease in LDL receptor activity.

Dietary fish oil plus lovastatin decreases both VLDL and LDL apo B production in miniature pigs.

Our previous apolipoprotein (apo) B kinetic studies of miniature pigs fed fish oil (Maxepa) demonstrated that very low density lipoprotein (VLDL) apo B concentrations were markedly reduced but that low density lipoprotein (LDL) concentrations were only modestly lowered because of a threefold increase in the conversion of VLDL apo B to LDL. In the present study, the effect of Maxepa plus lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on apo B metabolism was assessed. Miniature pigs (n = 6) were simultaneously injected with autologous 131I-VLDL and 125I-LDL after a diet of pig chow supplemented with 30 g/day of Maxepa and again after the addition of lovastatin, 30 mg/day. Kinetic data were analyzed by compartmental analysis with use of the CONSAM program. Compared with Maxepa alone, the addition of lovastatin reduced VLDL apo B concentrations by 21% (p less than 0.003) because of reduced VLDL apo B production (26%, p less than 0.005), as the fractional clearance rate was not affected. Conversion of VLDL apo B to LDL was reduced by 48% (p less than 0.005), and the direct removal of VLDL apo B from plasma was reduced by 25% (p less than 0.01). Maxepa plus lovastatin reduced LDL apo B concentrations by 44% (p less than 0.004). This was due to a 38% (p less than 0.002) decrease in LDL production, which was primarily derived from VLDL. The LDL apo B fractional catabolic rate was not significantly changed. Thus, a combination of Maxepa and lovastatin reduces both VLDL and LDL apo B concentrations, primarily by decreasing production rates.

Regulation of low density lipoprotein apoprotein B metabolism by lovastatin and cholestyramine in miniature pigs: effects on LDL composition and synthesis of LDL subfractions.

A major factor in the regulation of low density lipoprotein (LDL) apoprotein B (apo B) concentrations in miniature pigs is the direct synthesis of LDL apo B. LDL apo B derived from plasma very low density lipoproteins (VLDL) accounts for only 20% to 30% of total LDL synthesis. Treatment with lovastatin and cholestyramine can inhibit the direct synthesis pathway in this species, thereby lowering LDL apo B concentrations. The present study was carried out to determine if lovastatin alone was as effective as in combination with cholestyramine. The possibility that the direct synthesis pathway was confined to a specific subclass of LDL and the effect of lovastatin and cholestyramine on the metabolism of LDL subfractions were also investigated. Homologous 125I-VLDL and 131I-LDL were injected into miniature pigs during a control period and again following 18 days of treatment with lovastatin (1.2 mg/kg/d, n = 4) or in combination with cholestyramine (1.0 g/kg/d, n = 4). Kinetic analysis of apo B specific activity curves following lovastatin treatment indicated that LDL apo B pool size was decreased by 25% (P less than .025), which was due entirely to a 70% (P less than .025) decrease in the direct synthesis of LDL apo B, since VLDL-derived apo B, and LDL fractional catabolic rate (FCR) were not affected. Parameters of VLDL apo B metabolism were not affected. Lovastatin in combination with cholestyramine was more effective than lovastatin alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary fish oil increases conversion of very low density lipoprotein apoprotein B to low density lipoprotein.

Dietary fish oils, which are rich in omega-3 fatty acids, are known to produce a marked lowering of very low density lipoprotein (VLDL) triglyceride concentrations, but they have a less marked effect on low density lipoprotein (LDL) cholesterol. Our previous apolipoprotein (apo) B kinetic studies in miniature pigs demonstrated that conversion of VLDL apo B to LDL apo B accounted for 15% to 20% of total VLDL apo B catabolism. In addition, 75% to 80% of LDL apo B was derived independent of plasma VLDL or intermediate density lipoprotein (IDL) apo B catabolism. The present studies were carried out to determine if fish-oil diets influenced: 1) the conversion of VLDL to LDL, and 2) the pathways of LDL apo B synthesis. Autologous 125I-VLDL and 131I-LDL were injected into four pigs after both a corn-oil (30 g/day for 18 days) and a Maxepa (30 g/day for 18 days) dietary period. Analysis of apo B specific activity curves demonstrated that fish oil reduced the VLDL pool size by 38% (p less than 0.05) due to an increase in fractional catabolic rate (0.83 +/- 0.13 vs. 0.48 +/- 0.03 hr-1), as the synthesis rate was unaffected. However, the proportion of VLDL apo B converted to LDL increased significantly (56 +/- 7% vs. 17 +/- 3%, p less than 0.01) whereas the proportion cleared directly decreased (46 +/- 5% vs. 83 +/- 3%, p less than 0.005). Fish oil reduced total LDL apo B synthesis (0.6 +/- 0.1 vs. 1.1 +/- 0.2 mg/hr/kg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Mevinolin and cholestyramine inhibit the direct synthesis of low density lipoprotein apolipoprotein B in miniature pigs.

Previous studies established that following simultaneous injection of 125I-labeled homologous very low density lipoproteins (VLDL) and 131I-labeled homologous low density lipoproteins (LDL) into miniature pigs, a large proportion of LDL apolipoprotein B (apoB) was synthesized directly, independent of VLDL or intermediate density lipoprotein (IDL) apoB catabolism. The possibility that cholestyramine alone (a bile acid sequestrant) or in combination with mevinolin (a cholesterol synthesis inhibitor) could regulate the direct LDL apoB synthetic pathway was investigated. 125I-labeled VLDL and 131I-labeled LDL were injected into miniature pigs (n = 8) during a control period and following 18 days of cholestyramine treatment (1.0 g kg-1d-1) or following 18 days of treatment with cholestyramine and mevinolin (1.2 mg kg-1d-1). ApoB in each lipoprotein fraction was selectively precipitated using isopropanol in order to calculate specific activity. In control experiments, LDL apoB specific activity curves reached their peak values well before crossing the VLDL or IDL apoB curves. However, cholestyramine treatment resulted in LDL apoB curves reaching maximal values much closer to the point of intersection with the VLDL or IDL curves. Kinetic analyses demonstrated that cholestyramine reduced total LDL apoB flux by 33%, which was due entirely to inhibition of the LDL apoB direct synthesis pathway since VLDL-derived apoB was unaffected. In addition, the LDL apoB pool size was reduced by 30% and the fractional catabolic rate of LDL apoB was increased by 16% with cholestyramine treatment. The combination of mevinolin and cholestyramine resulted in an even more marked inhibition of the direct LDL apoB synthesis pathway (by 90%), and in two animals this pathway was completely abolished. This inhibition was selective as VLDL-derived LDL apoB synthesis was not significantly different. LDL apoB pool size was reduced by 60% due primarily to the reduced synthesis as well as a 40% greater fractional removal rate. These results are consistent with the idea that cholestyramine and mevinolin increase LDL catabolism by inducing hepatic apoB, E receptors. We have now shown that the direct synthesis of LDL apoB is selectively inhibited by these two drugs.

Direct synthesis of low-density lipoprotein apoprotein B in the miniature pig.

The metabolism of apoprotein B (apo B) was investigated in five miniature pigs following the injection of radiolabeled, very low-density lipoproteins (VLDL). The fractional catabolic rate (FCR) for VLDL apoprotein B was 0.71 +/- 0.10 h-1 (mean +/- SE), the rate of flux was 0.77 +/- 0.05 mg h-1 kg-1, and the pool size of apoprotein B averaged 1.26 +/- 0.20 mg kg-1. Examination of precursor-product relationships between VLDL and low-density lipoprotein (LDL) apoprotein B illustrated that a significant proportion (greater than 80%) of LDL apo B was derived from some source other than VLDL catabolism. In further experiments (n = 4), 125I-VLDL and 131I-LDL were simultaneously injected into miniature pigs. The fractional catabolic rate of LDL apo B averaged 0.055 +/- 0.008 h-1 and the flux rate 0.73 +/- 0.07 mg h-1 kg-1. These dual-label studies allowed us to calculate that an average of 16% of VLDL apoprotein B was converted to LDL and thus the remainder was cleared directly from the circulation. Simultaneous injection of radiolabeled homologous and human VLDL indicated that the catabolism of the two tracers was qualitatively similar. However, human VLDL apo B exhibited a slower fractional catabolic rate (0.42 v 0.71 h-1 P less than 0.05) and reduced rate of conversion to LDL. Therefore, low-density lipoproteins in the pig are largely produced by direct secretion into the circulation, independent of VLDL catabolism. Apo B metabolism in miniature pigs is similar to that of cynomologous and squirrel monkeys, and rats, but differs from normal humans in whom all LDL apo B is derived from VLDL catabolism.

Characterization and metabolic fate of two very-low-density lipoprotein subfractions separated by heparin-sepharose chromatography.

Human very-low-density lipoproteins (VLDL) have been separated into two discrete subfractions by heparin-Sepharose chromatography. The retained fraction relative to the unretained fraction is characterized by an increased cholesterol ester/triacylglycerol ratio and an increased ratio of apolipoprotein E relative to apolipoprotein C. We have subfractionated VLDL from type IV hyperlipoproteinemic subjects and characterized these subfractions with respect to (i) composition and (ii) the metabolic fate of apolipoprotein B of each subfraction. The unretained fraction accounted for an average of 42% of total VLDL in type IV subjects. A similar distribution was obtained with VLDL from Type III subjects; however, only 25% of normal VLDL is in the unretained fraction. The apolipoprotein E/apolipoprotein C ratio was 2-8-fold higher in the retained fraction. The distribution of apolipoprotein E isomorphs and the individual C apolipoproteins were similar in each fraction. Retained and unretained fractions were labelled with 125I and/or 131I and injected simultaneously into miniature pigs. Apolipoprotein B of retained fractions was catabolized at a greater rate (fractional catabolic rate = 0.98 h-1 vs. 0.54 h-1, n = 7, P less than 0.05) compared to unretained fractions. These results are consistent with the concept that reduced content of C apolipoproteins in VLDL is correlated with enhanced uptake by perfused rat livers. Apolipoprotein B from retained fractions was converted to intermediate-density lipoproteins (IDL) at a greater rate, and apolipoprotein B from both fractions were converted to low-density lipoproteins (LDL). Although the unretained fraction may be the precursor of the retained fraction, the possibility exists that each fraction is largely synthesized and catabolized independently.