Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men.

We investigated the effect of reduction in visceral obesity on the kinetics of apolipoprotein B-100 (apoB) metabolism in a controlled dietary intervention study in 26 obese men. Hepatic secretion of very low density lipoprotein (VLDL) apoB was measured using a primed, constant, infusion of 1-[13C]leucine. In seven men receiving the reduction diet, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) apoB kinetics were also determined. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry, and SAAM-II was used to estimate the fractional turnover rates. Subcutaneous and visceral adipose tissues at the L3 vertebra were quantified by magnetic resonance imaging. With weight reduction there was a significant decrease (P < 0.05) in body mass index, waist circumference, and visceral adipose tissue. The plasma concentrations of total cholesterol, triglyceride, insulin, and lathosterol also significantly decreased (P < 0.05). Compared with weight maintenance, weight reduction significantly decreased the VLDL apoB concentration, pool size, and hepatic secretion of VLDL apoB (delta+2.5+/-4.6 vs. delta-14.7+/-4.0 mg/kg fat free mass-day; P = 0.010), but did not significantly alter its fractional catabolism. Weight reduction was also associated with an increased fractional catabolic rate of LDL apoB (0.24+/-0.07 vs. 0.54+/-0.10 pools/day; P = 0.002) and conversion of VLDL to LDL apoB (11.7+/-2.5% vs. 56.3+/-11.4%; P = 0.008). A change in hepatic VLDL apoB secretion was significantly correlated with a change in visceral adipose tissue area (r = 0.59; P = 0.043), but not plasma concentrations of insulin, free fatty acids, or lathosterol. The data support the hypothesis that a reduction in visceral adipose tissue is associated with a decrease in the hepatic secretion of VLDL apoB, and this may be due to a decrease in portal lipid substrate supply. Weight reduction may also increase the fractional catabolism of LDL apoB, but this requires further evaluation.     

Mechanism of action of a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor on apolipoprotein B-100 kinetics in visceral obesity

We examined the effect of atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of apolipoprotein B-100 (apoB) metabolism in 25 viscerally obese men in a placebo-controlled study. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured using an iv bolus injection of [(2)H(3)]leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived by using a multicompartmental model (SAAM-II). Compared with the placebo group, atorvastatin treatment resulted in significant (P < 0.001) decreases in total cholesterol (-34%), triglyceride (-19%), LDL cholesterol (-42%), total apoB (-39%), and lathosterol (-86%); VLDL-apoB, IDL-apoB, and LDL-apoB pool sizes also fell significantly (P < 0.002) by -27%, -22%, and -41%, respectively. This was associated with an increase in the fractional catabolic rates of VLDL-apoB (+58%, P = 0.019), IDL-apoB (+40%, P = 0.049), and LDL-apoB (+111%, P = 0.001). However, atorvastatin did not significantly alter the production and conversion rates of apoB in all lipoproteins. We conclude that in obese subjects, atorvastatin decreases the plasma concentration of all apoB-containing lipoproteins chiefly by increasing their catabolism and not by decreasing their production or secretion. This may be owing to up-regulation of hepatic receptors as a consequence of inhibition of cholesterogenesis.     

Lipoprotein metabolism in subjects with hepatic lipase deficiency

A heritable deficiency of hepatic lipase (HL) provides insights into the physiologic function of HL in vivo. The metabolism of apolipoprotein B (apoB)-100 in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) and of apoA-I and apoA-II in high-density lipoprotein (HDL) particles lipoprotein (Lp)(AI) and Lp(AI:AII) was assessed in 2 heterozygous males for compound mutations L334F/T383M or L334F/R186H, with 18% and 22% of HL activity, respectively, compared with 6 control males. Subjects were provided with a standard Western diet for a minimum of 3 weeks. At the end of the diet period, apo kinetics was assessed using a primed-constant infusion of [5,5,5-(2)H(3)] leucine. Mean plasma triglyceride (TG) and HDL cholesterol levels were 55% and 12% higher and LDL cholesterol levels 19% lower in the HL patients than control subjects. A higher proportion of apoB-100 was in the VLDL than IDL and LDL fractions of HL patients than control subjects due to a lower VLDL apoB-100 fractional catabolic rate (FCR) (4.63 v 9.38 pools/d, respectively) and higher hepatic production rate (PR) (33.24 v 10.87 mg/kg/d). Delayed FCR of IDL (2.78 and 6.31 pools/d) and LDL (0.128 and 0.205 pools/d) and lower PR of IDL (3.67 and 6.68 mg/kd/d) and LDL 4.57 and 13.07 mg/kg/d) was observed in HL patients relative to control subjects, respectively. ApoA-I FCR (0.09 and 0.13 pools/d) and PR (4.01 and 6.50 mg/kg/d) were slower in Lp(AI:AII) particles of HL patients relative to control subjects, respectively, accounting for the somewhat higher HDL cholesterol levels. HL deficiency may result in a lipoprotein pattern associated with low heart disease risk.     

Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder characterized by low levels of apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol. Decreased production rates of apoB have been demonstrated in vivo in FHBL heterozygotes. In the present study, we wished to investigate whether the transport of triglycerides was similarly affected in these subjects. Therefore, we studied the in vivo kinetics of very-low-density lipoprotein (VLDL) triglycerides and VLDL apoB-100 simultaneously in 7 FHBL heterozygotes from 2 well-characterized kindreds and 7 healthy normolipidemic subjects. In both kindreds, hypobetalipoproteinemia is caused by mutations in the 5' portion of the apoB gene specifying short truncations of apoB undetectable in plasma. A bolus injection of deuterated palmitate and a primed constant infusion of deuterated leucine were given simultaneously, and their incorporation into VLDL triglycerides and VLDL apoB, respectively, were determined by gas chromatography-mass spectrometry. Kinetic parameters were calculated by using compartmental modeling. VLDL apoB fractional catabolic rates (FCRs) in FHBL heterozygotes and controls were similar (11. 6+/-3.9 and 10.9+/-2.4 pools per day, respectively, P=0.72). On the other hand, FHBL heterozygotes had a 75% decrease in VLDL apoB production rates compared with normal subjects (5.8+/-1.8 versus 23.4+/-7.1 mg/kg per day, P<0.001). The decreased production rates of VLDL apoB accounts for the very low concentrations of plasma apoB found in heterozygotes from these kindreds (24% of normal). Mean VLDL triglyceride FCRs in FHBL subjects and controls were not significantly different (1.06+/-0.74 versus 0.89+/-0.50 pools per hour, respectively, P=0.61). There was a good correlation between VLDL apoB FCR and VLDL triglyceride FCR in the 2 groups (r=0.84, P<0. 001). VLDL triglyceride production rates were decreased by 60% in FHBL heterozygotes compared with controls (9.3+/-6.0 versus 23.0+/-9. 6 micromol/kg per hour, P=0.008). Thus, the hepatic secretion of VLDL triglycerides is reduced in FHBL heterozygotes but to a lesser extent than the decrease in apoB-100 secretion. This is probably achieved by the secretion of VLDL particles enriched with triglycerides.     

Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates

Subjects with moderate combined hyperlipidemia (n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL(1)) apoB (4.52+/-3.06 pools per day on atorvastatin; 5.48+/-4.76 pools per day on simvastatin versus 2.26+/-1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL(1) concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL(1) to VLDL(2) and of VLDL(2) to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54+/-0.30 pools per day at baseline to 1.17+/-0.87 pools per day on atorvastatin and to 0.95+/-0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58-84% by statin treatment (P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22+/-0.04 pools per day) increased to 0.44+/-0.11 pools per day on atorvastatin and 0.38+/-0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.     

Dose-dependent effect of rosuvastatin on apolipoprotein B-100 kinetics in the metabolic syndrome

In a randomized, double-blind, crossover trial of 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week placebo wash-outs between treatments, the dose-dependent effect of rosuvastatin on apolipoprotein (apo) B-100 kinetics in metabolic syndrome subjects were studied. Compared with placebo, there was a significant dose-dependent decrease with rosuvastatin in plasma cholesterol, triglycerides, LDL cholesterol, apoB and apoC-III concentrations and in the apoB/apoA-I ratio, lathosterol:cholesterol ratio, HDL cholesterol concentration and campesterol:cholesterol ratio also increased significantly. Rosuvastatin significantly increased the fractional catabolic rates (FCR) of very-low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and LDL-apoB and decreased the corresponding pool sizes, with evidence of a dose-related effect. LDL apoB production rate (PR) fell significantly with rosuvastatin 40 mg/day with no change in VLDL and IDL-apoB PR. Changes in triglycerides were significantly correlated with changes in VLDL apoB FCR and apoC-III concentration, and changes in lathosterol:cholesterol ratio were correlated with changes in LDL apoB FCR, the associations being more significant with the higher dose of rosuvastatin. In the metabolic syndrome, rosuvastatin decreases the plasma concentration of apoB-containing lipoproteins by a dose-dependent mechanism that increases their rates of catabolism. Higher dose rosuvastatin may also decrease LDL apoB production. The findings provide a dose-related mechanism for the benefits of rosuvastatin on cardiovascular disease in the metabolic syndrome.     

Apolipoprotein B-100 kinetics in visceral obesity: associations with plasma apolipoprotein C-III concentration

Obesity is strongly associated with dyslipidemia, which may account for the associated increased risk of atherosclerosis and coronary disease. We aimed to test the hypothesis that kinetics of hepatic apolipoprotein B-100 (apoB) metabolism are disturbed in men with visceral obesity and to examine whether these kinetic defects are associated with elevated plasma concentration of apolipoprotein C-III (apoC-III). Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured in 48 viscerally obese men and 10 age-matched normolipidemic lean men using an intravenous bolus injection of d(3)-leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry (GCMS). Kinetic parameters were derived using a multicompartmental model (Simulation, Analysis, and Modeling Software II [SAAM-II]). Compared with controls, obese subjects had significantly elevated plasma concentrations of plasma triglycerides, cholesterol, LDL-cholesterol, VLDL-apoB, IDL-apoB, LDL-apoB, apoC-III, insulin, and lathosterol (P <.01). VLDL-apoB secretion rate was significantly higher (P =.034) in obese than control subjects; the fractional catabolic rates (FCRs) of IDL-apoB and LDL-apoB (P <.01) and percent conversion of VLDL-apoB to LDL-apoB (P <.02) were also significantly lower in obese subjects. However, the decreased VLDL-apoB FCR was not significantly different from the lean group. In the obese group, plasma concentration of apoC-III was significantly and positively associated with VLDL-apoB secretion rate and inversely with VLDL-apoB FCR and percent conversion of VLDL to LDL. In multiple regression analysis, plasma apoC-III concentration was independently and significantly correlated with the secretion rate of VLDL-apoB (regression coefficient [SE] 0.511 [0.03], P =.001) and with the percent conversion of VLDL-apoB to LDL-apoB (-0.408 [0.01], P =.004). Our findings suggest that plasma lipid and lipoprotein abnormalities in visceral obesity may be due to a combination of overproduction of VLDL-apoB particles and decreased catabolism of apoB containing particles. Elevated plasma apoC-III concentration is also a feature of dyslipidemia in obesity that contributes to the kinetic defects in apoB metabolism.     

Pravastatin sodium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreases serum total cholesterol in Japanese White rabbits by two different mechanisms

Pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), when orally administered to male Japanese White (JW) rabbits at 1-30 mg/kg for 21 days, decreased the concentrations of total cholesterol, low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol in a dose-dependent manner. On the other hand, pravastatin did not change the concentration of serum triglycerides and very low density lipoprotein (VLDL)-cholesterol. On day 21, LDL-cholesterol was significantly decreased at doses higher than 3 mg/kg, whereas HDL-cholesterol was significantly reduced at doses higher than 10 mg/kg. The concentrations of hepatic LDL receptor proteins determined by immunoblot analysis increased at the same dose at which the concentrations of LDL-cholesterol decreased. The serum concentrations of HDL-cholesterol were decreased at the same dose at which VLDL-cholesterol secretion rates from the liver were reduced. The present study suggests that in JW rabbits, pravastatin decreases the serum concentration of LDL-cholesterol through an LDL receptor pathway, whereas the agent lowers the concentration of HDL-cholesterol by the mechanisms associated with a reduction of VLDL-cholesterol secretion from the liver.     

Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs.

The hypolipidemic effect of NK-104 and its mechanisms of action (effects on hepatic sterol synthesis, low density lipoprotein (LDL)-receptor expression and very low density lipoprotein (VLDL) secretion) were studied in guinea pigs using simvastatin as a reference substance. There was a dose-dependent and significant reduction of both plasma total cholesterol (17.4, 24.5 and 45.3% at 0.3, 1 and 3 mg/kg, respectively) and triglycerides (21.1 and 32.2% at 1 and 3 mg/kg, respectively) after 14-day administration of NK-104. Simvastatin at 30 mg/kg lowered plasma total cholesterol (25.0%) but not triglyceride levels. NK-104 (3 mg/kg) and simvastatin (30 mg/kg) inhibited hepatic sterol synthesis by approximately 80%, 3 h after dosing, and enhanced LDL receptor binding-capacity of liver membranes 1.5-fold after 14-day dosing. The former group accelerated LDL clearance somewhat more markedly than the latter, and increased fractional catabolic rate 1.8-fold (vs. 1.4-fold). Furthermore, only the NK-104 (3 mg/kg) suppressed VLDL secretion into the liver perfusate (triglyceride. 19.9%; apoB, 24.2%) with extensive reduction of hepatic sterol synthesis caused by prolonged action. These results indicate that NK-104 and simvastatin at 10 times the dosage of the former, similarly enhances hepatic LDL receptor; however, only NK-104 with prolonged action suppresses VLDL secretion to show higher cholesterol-lowering potency and triglyceride-reducing effect.     

Reduction of Plasma Cholesterol Levels and Induction of Hepatic LDL Receptor by Cerivastatin Sodium (CAS 143201-11-0, BAY w 6228), a New Inhibitor of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, in Dogs

The effects of cerivastatin sodium (BAY w 6228), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma cholesterol concentrations and the induction of hepatic LDL receptors were investigated with beagle dogs and Hep G2 cells. Oral administration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 weeks reduced plasma total and very low-density lipoprotein plus low-density lipoprotein (VLDL + LDL) cholesterol concentrations and increased hepatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepatic LDL receptors in cerivastatin-treated animals. Similar results were obtained by administration of pravastatin (1.0 and 5.0 mg/kg/day) for 3 weeks. Binding activity of the LDL receptor, as well as receptor mRNA and protein concentrations, were increased in a dose-dependent manner (0.01–1.0 μM) by exposure of Hep G2 cells to cerivastatin. The results suggest that cerivastatin reduces plasma cholesterol concentrations by increasing hepatic LDL receptor expression. The mechanism of lowering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the effects with cerivastatin were apparent at doses much lower than the effective doses of the other drugs. Cerivastatin, therefore, shows potential for clinical use as a potent and efficacious plasma cholesterol-lowering drug. This revised version was published online in July 2006 with corrections to the Cover Date.     

Effects of short- and long-term growth hormone replacement on lipoprotein composition and on very-low-density lipoprotein and low-density lipoprotein apolipoprotein B100 kinetics in growth hormone-deficient hypopituitary subjects

In this study, we concurrently examined the effects of 8 and 40 weeks of growth hormone replacement (GHR) on lipids, lipoprotein composition, low-density lipoprotein (LDL) size, very-low-density lipoprotein (VLDL) apolipoprotein (apo)B kinetics and LDL apoB kinetics. Eight weeks of GHR did not alter lipid profiles. Forty weeks of GHR increased high-density lipoprotein-cholesterol (HDL-C) concentration (P =.01), nonsignificantly reduced LDL-C (P =.06), and reduced the HDL/LDL-C ratio (P =.04). Forty weeks of GHR increased HDL free cholesterol (P =.03), total cholesterol (P =.01), and cholesterol ester (P <.01) concentrations. No other significant changes in VLDL, LDL, or HDL composition or LDL size were noted at any time. Eight weeks of GHR reduced VLDL apoB absolute secretion rate (ASR, P =.03), with nonsignificant reductions in fractional secretion rate (FSR, P =.09) and pool size (P =.09). After 40 weeks of GHR, the VLDL apoB ASR, FSR, and pool size were not significantly different from baseline. Forty weeks of GHR increased both LDL apoB FSR (P =.02) and LDL apoB ASR (P =.04), with a small decrease in pool size. Thus, GHR may have important antiatherogenic effects; HDL-C increased, LDL-C was nonsignificantly reduced, the total/HDL-C ratio was reduced, VLDL apoB production was reduced, and LDL apoB turnover was increased.     

Kinetics of very-low-density lipoprotein apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies

To further explore the physiology of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P < .001) of the hepatic secretion of apoB, which was higher in the fed state compared with the fasted state (1,819 +/- 188 v 1,046 +/- 61 mg/d, P < .001). In the fed state, apoB secretion increased with age (P = .003) and tended to be higher in men compared with women (P = .0065). The fractional catabolism of VLDL apoB decreased with weight (P = .0038) and was lower in men versus women (8.38 +/- 0.55 v 12.59 +/- 1.65 pools/d, P = .007), as well as patients that were carriers of the E4 allele compared with those who were not carriers of this allele (5.52 +/- 0.49 v 9.58 +/- 0.87 pools/d, P < .001). The VLDL apoB concentration in both the fed and fasted states was dependent on both the rate of hepatic production and fractional clearance of apoB. Plasma cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations in the fasted state were principally determined by the fractional catabolism of VLDL apoB (P< .005). These findings suggest that under physiologic conditions in healthy individuals, the transport of VLDL apoB in plasma is predominantly determined by age, sex, body weight, apoE genotype, and prandial status.     

Effect of low-density lipoprotein apheresis on kinetics of apolipoprotein B in heterozygous familial hypercholesterolemia

The acute reduction of low-density lipoprotein (LDL) cholesterol obtained by LDL-apheresis allows the role of the high level of circulating LDL on lipoprotein metabolism in heterozygous familial hypercholesterolemia (heterozygous FH) to be addressed. We studied apolipoprotein B (apoB) kinetics in five heterozygous FH patients before and the day after an apheresis treatment using endogenous labeling with [(2)H(3)]leucine. Compared with younger control subjects, heterozygous FH patients before apheresis showed a significant decrease in the fractional catabolic rate of LDL (0.24 +/- 0.08 vs. 0.65 +/- 0.22 day(-1); P < 0.01), and LDL production was increased in heterozygous FH patients (18.9 +/- 7.0 vs. 9.9 +/- 4.2 mg/kg.day; P < 0.05). The modeling of postapheresis apoB kinetics was performed using a nonsteady state condition, taking into account the changing pool size of very low density lipoprotein (VLDL), intermediate density lipoprotein, and LDL apoB. The postapheresis kinetic parameters did not show statistical differences compared with preapheresis parameters in heterozygous FH patients; however, a trend for increases in fractional catabolic rate of LDL (0.24 +/- 0.08 vs. 0.35 +/- 0.09 day(-1); P = 0.067) and the production of VLDL (13.7 +/- 8.3 vs. 21.9 +/- 1.6 mg/kg.day; P = 0.076) was observed. These results suggested that the marked decrease in plasma LDL obtained a short time after LDL-apheresis is able to stimulate LDL receptor activity and VLDL production in heterozygous FH.     

HMG-CoA reductase inhibitors: a brief review of their pharmacological properties and clinical efficacy in cardiovascular disease]

The results of recently published studies on primary and secondary prevention of coronary heart disease with HMG-CoA reductase inhibitors--statins--support their use in patients with primary hypercholesterolaemia or mixed hyperlipidaemia, with or without atherosclerotic vascular disease. From a pharmacological point of view, statins inhibit HMG-CoA reductase, reduce the endogenous synthesis of cholesterol and increase the apoB/apoE lipoprotein clearance from plasma. Recent studies confirm that HMG-CoA reductase inhibitors may also decrease hepatic production of VLDL and LDL-cholesterol. However, they have different pharmacokinetic properties and variable effectiveness with potential clinical implications. These drugs are generally well tolerated with a similar profile of adverse effects (gastrointestinal effects, hepatic dysfunction and myopathy). The knowledge of their pharmacodynamic and pharmacokinetic properties can lead to a rational use and greater understanding of their potential benefits.     

Effects of rosiglitazone and pioglitazone on lipoprotein metabolism in patients with Type 2 diabetes and normal lipids

Aims Previous studies have suggested that plasma lipids are affected differently by the peroxisome proliferators‐activated receptor (PPAR)‐γ agonists pioglitazone and rosiglitazone. The aim of this study was to perform a quantitative lipoprotein turnover study to determine the effects of PPAR‐γ agonists on lipoprotein metabolism. Methods Twenty‐four subjects with Type 2 diabetes treated with diet and/or metformin were randomized in a double‐blind study to receive 30 mg pioglitazone, 8 mg rosiglitazone or placebo once daily for 3 months. Before and after treatment, absolute secretion rate (ASR) and fractional catabolic rate (FCR) of very low‐density lipoprotein (VLDL), intermediate‐density lipoprotein (IDL) and low‐density lipoprotein (LDL) apolipoprotein B100 were measured with a 10‐h infusion of 1‐¹³C leucine. Results There was a significant decrease in glycated haemoglobin (HbA_1c) and non‐esterified fatty acids with pioglitazone (P = 0.01; P = 0.02) and rosiglitazone (P = 0.04; P = 0.003), respectively, but no change in plasma triglyceride or high‐density lipoprotein (HDL) cholesterol. Following rosiglitazone, there was a significant reduction in VLDL apolipoprotein B100 (apoB) ASR (P = 0.01) compared with baseline, a decrease in VLDL triglyceride/apoB (P = 0.01), an increase in LDL2 cholesterol (P = 0.02) and a decrease in LDL3 cholesterol (P = 0.02). There was a decrease in VLDL triglyceride/apoB (P = 0.04) in the pioglitazone group. There was no significant difference in change in VLDL ASR or FCR among the three groups. Conclusions In patients with Type 2 diabetes and normal lipids, treatment with rosiglitazone or pioglitazone had no significant effect on lipoprotein metabolism compared with placebo.     

Hepatic cholesterol metabolism in estrogen-treated men.

Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men.     

Lipid and apolipoprotein levels and distribution in patients with hypertriglyceridemia: effect of triglyceride reductions with atorvastatin

Atorvastatin is a new hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor that has been demonstrated to be efficacious in reducing both triglyceride (TG) and cholesterol (CHOL) levels in humans. Twenty-seven (N = 27) patients with primary hypertriglyceridemia (TG > 350 mg/dL) were studied before and after 4 weeks on atorvastatin treatment at a dosage of either 20 (n = 16) or 80 (n = 11) mg/d. The present report examines changes in the plasma levels of several apolipoproteins, including apolipoprotein C-II (apoC-II), apoC-III, and apoE, after atorvastatin. Dose-dependent reductions in both CHOL (20.3% v 43.1%) and TG (26.5% v 45.8%) for the low and high dose, respectively, have been reported in these individuals. In addition to the reductions in apoB commonly associated with the use of HMG-CoA reductase inhibitors, significant reductions in apoE (37% and 49%), apoC-II (28% and 42%), and apoC-III (18% and 30%) were observed with this agent at the 20- and 80-mg/d dosage, respectively. Using fast protein liquid chromatography (FPLC) to fractionate whole plasma according to particle size, the effect of atorvastatin on lipid and apolipoprotein distribution in 20 lipoprotein fractions was also determined. Our results indicate that after 4 weeks on atorvastatin, (1) there was a 2-fold increase in the CHOL content as assessed by the CHOL/apoB ratio for 13 subfractions from very-low-density lipoprotein (VLDL) to small low-density lipoprotein (LDL); (2) there was a statistically significant reduction in the percentage of plasma apoB associated with VLDL-sized particles (30.5% v 26.8%); (3) there was a preferential reduction in plasma apoE from non-apoB-containing lipoproteins with treatment; (4) the losses of apoC-II and apoC-III, on the other hand, were comparable for all lipoprotein fractions; and (5) the fraction of plasma TG associated with HDL was increased after treatment. These changes in lipids and apolipoproteins did not depend on the dose of atorvastatin. There was, on the other hand, a dose-dependent reduction in cholesteryl ester transfer protein (CETP) activity, defined as the percentage of 3H-cholesteryl oleate transferred from high-density lipoprotein (HDL) to LDL. CETP activity was reduced by 10.3% and 26.4% with the low and high dose of atorvastatin. Together, these composition data would be consistent with a net reduction in the number of TG-rich lipoproteins that may be explained by (1) a reduction in VLDL synthesis, (2) a preferential removal of VLDL without conversion to LDL, and (3) a preferential accelerated removal of a subpopulation of LDL.     

Effect of cholesterol reducing therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on secondary prevention after myocardial infarction in Japanese patients

Lowering the blood cholesterol level is a safe method to improve survival for primary and secondary prevention of coronary heart disease. However, there is no evidence for any effectiveness in Japanese. This study was designed to evaluate the effect of cholesterol lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor on cardiac events(death and reinfarction) in Japanese patients after myocardial infarction. A total of 290 patients after myocardial infarction were studied retrospectively. The patients were divided into 2 groups with or without HMG-CoA reductase inhibitor therapy for lowering blood cholesterol levels. The cumulative cardiac events and percentage change of cholesterol levels[total cholesterol and low-density lipoprotein (LDL) cholesterol level] were compared between the 2 groups. HMG-CoA reductase inhibitor therapy lowered plasma cholesterol levels significantly (total cholesterol level--11 +/- 20%, LDL cholesterol level--23 +/- 26%) in patients with hypercholesterolemia, whereas there was no change(total cholesterol level 4.3 +/- 22%, LDL cholesterol level--7.2 +/- 24%) in patients without hypercholesterolemia. HMG-CoA reductase inhibitor therapy reduced cardiac events significantly compared in patients with hypercholesterolemia(p = 0.0008), but there was no benefit in patients without hypercholesterolemia. We suggest that treatment with HMG-CoA reductase inhibitor therapy for lowering cholesterol levels was effective for secondary prevention after myocardial infarction in Japanese patients with hypercholesterolemia.     

Insulin and the metabolism of lipoproteins

In normal individuals, insulin regulates lipoprotein metabolism. It increases hepatic triglycerides (TG) secretion and makes VLDL and chylomicrons post prandial removal easy by stimulating adipose tissue lipoprotein lipase (LPL). Insulin activity and cholesterol rich lipoprotein is more complicated: by its action on VLDL and chylomicrons turn-over, it influences LDL and HDL formation. It regulates cellular cholesterol pool at different levels: stimulation of LDL receptor, but also of HMG CoA reductase. Controlling LCAT, in participates in cholesterol removal by HDL. In insulin dependent diabetes, lack of adipose tissue LPL stimulation augments triglycerid-rich lipoproteins, by slowing their catabolism, resulting in a weak increase of LDL and a lowering of HDL. In non insulin dependent diabetes with hyperinsulinism, VLDL are elevated because of insulin stimulation of triglycerid hepatic production. LDL are increasing. HDL status remains discussed: HDL cholesterol is low but HDL triglycerid is high, there is no known disturbance of apo A level. In the two types of diabetes, although mechanism is different, perturbation of lipoprotein metabolism may account for the atherogenicity of this disorders.