VLDL apoB Research Articles

4.P.251 Inhibition of ACAT by CI-1011, in vivo, decreases both VLDL and LDL apoB production in the miniature pig

4.P.251 Inhibition of ACAT by CI-1011, in vivo, decreases both VLDL and LDL apoB production in the miniature pig

Production of apolipoprotein B-67 in apolipoprotein B-67/B-100 heterozygotes: technical problems associated with leucine contamination in stable isotope studies

In vivo kinetics of apoB were performed in three apoB-67/apoB-100 heterozygotes using a primed-constant infusion of (5,5,5-(2)H3)-leucine. Mean plasma VLDL and LDL apoB-67 concentrations were 0.05 +/- 0.01 mg/dl and 0.62 +/- 0.17 mg/dl, respectively, which were 0.2% and 2.8% of total plasma apoB concentrations. When cation exchange chromatography was used to separate plasma amino acids from fragments of polyacrylamide gels, the tracer/tracee ratio at plateau for VLDL apoB-67 was less than 50% of that observed when centrifugation was used. Mean fractional catabolic rate for LDL apoB-67 was 2-fold higher when the lower plateau was used in multicompartmental analysis compared to the higher plateau (0.70 +/- 0.21 versus 0.37 +/- 0.06 pools per day, P = 0.06). The lower plateau resulted from introduction of unlabeled leucine during cation exchange chromatography; therefore, all samples were processed with centrifugation. Mean fractional catabolic rates for VLDL and LDL apoB-67 were not significantly different from VLDL and LDL apoB-100 (VLDL: 9.7 +/- 3.4 versus 18.1 +/- 8.6 pools per day, respectively, P = 0.19; LDL: 0.37 +/- 0.06 versus 0.34 +/- 0.11 pools per day, respectively, P = 0.66). Mean secretion rate of VLDL apoB-67 was 5.6% of VLDL apoB-100 (0.20 +/- 0.04 versus 3.6 +/- 1.3 mg/kg/day, P = 0.01). Fifty-three % of apoB-67 was directly removed from VLDL compared to only 3.5% of apoB-100 (P = 0.003), thus accounting for the lower proportion of apoB-67 in LDL (3.3 +/- 1.8%) as compared to VLDL (11.2 +/- 2.5%). Mean LDL production rate for apoB-67 was 2.6% of LDL apoB-100 (0.09 +/- 0.02 versus 3.50 +/- 1.39 mg/kg/day, P = 0.05). Thus, decreased secretion of apoB-67 is responsible for low levels of apoB-67.

Plasma Acylation-Stimulating Protein in Coronary Artery Disease

To date, plasma levels of acylation-stimulating protein (ASP) have been determined only in normal and obese individuals. Accordingly. ASP was measured in fasting samples obtained from 59 age-matched controls and 208 patients with documented coronary artery disease (CAD). Overall, plasma ASP was significantly higher in the CAD subjects compared to the control subjects (55.3 +/- 1.8 nmol/L CAD versus 32.0 +/- 2.6 nmol/L control, P < .0005). In the control group, the distribution of plasma ASP values was unimodal whereas in the coronary group it was significantly skewed to the right. The coronary group was subdivided into those with pronounced elevation of apoB (a marked type II phenotype, n = 13), those with hypertriglyceridemia with a normal apoB (n = 17), and the remaining CAD subjects (n = 178). In the first two groups, ASP did not differ significantly from control subjects (43 +/- 2.8 nmol/L and 49 +/- 4.4 nmol/L respectively). By contrast, in the remaining CAD subjects, both the mean ASP level (56.8 +/- 2.0 nmol/L, P < .001 by ANOVA) and the proportion of patients with a markedly elevated ASP (25.3% were > 95th percentile, P < .005 versus control by X2) were significantly increased. When this third group was divided into tertiles by plasma apoB and triglyceride there was a direct relationship between plasma ASP and these two parameters. Linear regression analysis demonstrated an association between plasma ASP and plasma triglyceride (P < .05), VLDL cholesterol (P < .025), and VLDL apoB (P < .05). Finally, when all of the CAD subjects were divided by apoE phenotype, there appeared to be a relationship between plasma ASP and apoE phenotype such that ASP was higher in E2 subjects, intermediate in E3 subjects, and lower in E4 subjects. The present data document plasma ASP levels in a number of dyslipoproteinemic states and suggest a relation between the adipsin-ASP pathway and other metabolic determinants of lipoprotein metabolism.

Lipoprotein kinetics in patients with analbuminemia. Evidence for the role of serum albumin in controlling lipoprotein metabolism.

In vitro data suggested that albumin is a key factor controlling apolipoprotein (apo) synthesis by hepatocytes. Studies in analbuminemic rats have shown an increase in secretion of apoB-containing lipoprotein from the liver. We studied the kinetic aspects of apoB- and apoAI-containing lipoprotein metabolism in two sisters with analbuminemia using a constant 14-hour infusion of leucine labeled with stable isotopes. Compared with control subjects, total cholesterol was higher in the two patients (432 and 461 versus 155 +/- 14 mg/dL), as was apoB (257 and 230 versus 72 +/- 7 mg/dL). Triglycerides were slightly increased (134 and 105 versus 89 +/- 9 mg/dL), whereas apoAI was lower (109 and 105 versus 124 +/- 6 mg/dL). VLDL-apoB production was higher, as was the production of IDL-apoB and LDL-apoB (32.8 and 36.0 versus 24.8 +/- 5.9, 32.1 and 27.2 versus 16.4 +/- 2.3, and 14.1 and 17.6 versus 10.3 +/- 1.2 mg.kg-1.d-1, respectively). The fractional catabolic rate of all the apoB-containing lipoproteins was decreased (0.23 and 0.37 versus 0.48 +/- 0.05, 0.27 and 0.28 versus 0.62 +/- 0.08, and 0.012 and 0.009 versus 0.022 +/- 0.002.h-1, respectively). A similar mechanism could explain the dyslipidemia observed in other conditions associated with low albumin levels, such as nephrotic syndrome.

Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes.

Apolipoprotein (apo) B-67 is a truncated form of apoB-100 due to deletion of an adenine at cDNA 9327. Heterozygotes have one allele making apoB-100; therefore, plasma apoB levels would be predicted to be at least 50% of normal. However, apoB-67 heterozygotes have total plasma apoB levels that are 24% of normal. To determine the mechanisms responsible for the lower-than-expected levels of apoB, in vivo kinetics of apoB-100 were performed in three apoB-67/apoB-100 heterozygotes and compared with those of six control subjects by using a primed-constant infusion of [5,5,5-2H3]leucine in the fed state. Kinetic parameters were calculated by multicompartmental modeling of the data. The mean total apoB plasma concentration of the apoB-67 subjects was 21.8+/-6.1 mg/dL, or 24% of that of control subjects (89.6+/-24.1 mg/dL, P=.002). ApoB-67 subjects had lower mean VLDL apoB-100 production rates (3.6+/-1.2 versus 13.9+/-3.5 mg x kg(-1) x d(-1), P=.002) and lower mean transport rates of apoB-100 into LDL (3.5+/-1.4 versus 12.6+/-4.1 mg x kg(-1) x d(-1), P=.008) compared with control subjects. The transport rate into IDL was not significantly different (1.2+/-0.5 versus 6.2+/-4.0 mg x kg(-1) x d(-1), P=.07). The fractional catabolic rate of VLDL apoB-100 was significantly higher in apoB-67 subjects than in control subjects (18.1+/-8.6 versus 7.6+/-1.6 mg x kg(-1) x d(-1), P=.017). ApoB-100 IDL and LDL fractional catabolic rates were not significantly different. VLDL apoB-100 pool size in apoB-67 subjects was 11% of that of control subjects (15.8+/-7.7 versus 141.6+/-33.7 mg, P=.0004) due to a 74% lower production rate (26% of control values) and a 2.4-fold higher fractional catabolic rate. LDL apoB-100 pool size in apoB-67 subjects was 22% of that of control subjects (665.3+/-192.4 versus 2968.3+/-765.2 mg, P=.002) due primarily to a lower production rate (27% of control values). Thus, both decreased production of VLDL and LDL apoB-100 and increased catabolism of VLDL apoB-100 are responsible for the low levels of apoB-100 in apoB-67 subjects.

Hypocholesterolemic actions of atorvastatin are associated with alterations on hepatic cholesterol metabolism and lipoprotein composition in the guinea pig

Guinea pigs were fed 15% (w/W) fat, high in lauric and myristic acids, a diet known to produce hypercholesterolemia in these animals. The diet was given alone or in combination with four doses of atorvastatin equivalent to 1, 3, 10, and 20 mg/kg per day. Atorvastatin reduced plasma LDL cholesterol concentrations by 46, 50, 53, and 70%, respectively (P < 0.001). Plasma apoB concentrations were reduced by atorvastatin (P < 0.001) and compositional changes occurred in VLDL and LDL with reductions of the relative proportion of cholesteryl ester and increases in triacylglycerol. A reduction in hepatic cholesteryl ester (66%) was observed only with the highest atorvastatin dose (20 mg/kg per day) while microsomal cholesterol was reduced by 30% with 3-20 mg/kg per day. Hepatic ACAT activity was down-regulated and apoB/E receptor number was increased by atorvastatin. In contrast, HMG-CoA reductase activity and cholesterol 7 alpha-hydroxylase were not affected by the drug. VLDL apoB secretion rates were decreased by atorvastatin treatment 59 and 76% with 3 and 20 mg/kg per day, respectively. Nascent VLDL particles were larger after drug treatment, showing an increased number in triacylglycerol molecules. These results support the hypothesis that the plasma LDL lowering induced by atorvastatin is due to a decreased secretion of apoB in combination with an increase of hepatic apoB/E receptors.

Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state.

The role of hyperinsulinemia in the pathogenesis of triglyceride (TG) and VLDL over-production in insulin-resistant states remains controversial. While studies in humans and animals have generally suggested that chronic hyperinsulinemia facilitates VLDL production, particularly in the presence of an abundant supply of substrate for VLDL synthesis, the majority of in vitro studies using cultured hepatocytes and hepatoma cell lines have demonstrated an acute inhibitory effect of insulin. Using radiolabeled VLDL tracers we have examined the acute effect of hyperinsulinemia on VLDL production in humans. We found a rapid suppression of plasma free fatty acid (FFA) levels in response to insulin and a consistent 50-60% insulin-induced suppression of both VLDL TG and VLDL apolipoprotein (apo) B in lean insulin-sensitive individuals. Elevation of plasma FFA levels by infusing heparin and Intralipid without hyperinsulinemia resulted in a marked increase in VLDL TG and VLDL apoB production. When the insulin-induced suppression of plasma FFA levels was prevented during hyperinsulinemia, VLDL TG production was still inhibited, although to a lesser extent than with insulin alone. We concluded from these findings that insulin suppresses VLDL production in insulin-sensitive humans partly by suppressing plasma FFA levels and partly by a non-FFA-mediated (perhaps direct hepatic) mechanism. In addition, we found that chronically insulin-resistant hyperinsulinemic obese individuals were resistant to this suppressive effect of insulin on VLDL apoB production, in keeping with similar findings by others performing in vitro experiments using cultured hepatocytes isolated from insulin-resistant or hyperinsulinemic rats. The relevance of these findings to the mechanism of hypertriglyceridemia associated with chronic insulin-resistant states in humans remains a matter of speculation. One hypothesis is that resistance to the normal suppressive effect of insulin, in association with other metabolic abnormalities associated with insulin resistance, may contribute to postprandial and postabsorptive hypertriglyceridemia.

ApoA-II kinetics in humans using endogenous labeling with stable isotopes: slower turnover of apoA-II compared with the exogenous radiotracer method

ApoA-II is a major apolipoprotein constituent of high density lipoproteins (HDL) and may play an important role in lipoprotein metabolism and predisposition to atherosclerosis. Previous radiotracer kinetic studies have suggested that the metabolism of apoA-II in humans may be different than the metabolism of apoA-I, the major HDL apolipoprotein. In the present study, we have used an endogenous labeling technique using stable isotopically labeled amino acids to study apoA-II metabolism and compared the results to those obtained by a simultaneous exogenous radiotracer labeling method. Seven subjects with HDL cholesterol levels ranging from 9 to 93 mg/dl and apoA-II levels from 13 to 60 mg/dl were investigated in this study. [13C6]phenylalanine and 131I-labeled apoA-II were simultaneously administered as a primed-constant infusion and a bolus injection, respectively. In the endogenous labeling study, plateau tracer/tracee ratios of VLDL apoB-100 were used as estimates for the precursor pool tracer/tracee ratios for apoA-II synthesis. Residence times of apoA-II using these two independent methods were found to be highly correlated (r = 0.973, P < 0.0002). These results indicate that the endogenous labeling of apoA-II using stable isotopically labeled amino acids is a reasonable alternative to the conventional exogenous radiotracer labeling method for the investigation of apoA-II turnover. However, under the conditions of our experimental design and modeling strategy, the apoA-II residence times as determined by endogenous labeling were significantly longer (mean 5.33 days) than by exogenous radiotracer (mean 4.65 days). This suggests that apoA-II turnover may be even slower than believed based on radiotracer studies, and further supports the concept that HDL containing apoA-II are metabolized differently than HDL without apoA-II.

Effects of Colestipol Alone and in Combination With Simvastatin on Apolipoprotein B Metabolism

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).

KIDNEY-PANCREAS TRANSPLANTATION

We have previously shown that both kidney-alone and combined kidney-pancreas transplantation lower VLDL and IDL apoB while increasing LDL apoB, apoA-I, and HDL free cholesterol (FC). In this report, we analyze the lipoproteins of 31 patients who have undergone combined kidney-pancreas transplantation. Systemic venous drainage of the pancreas was utilized in 20 of these patients while 11 had portal venous drainage. Six lipoprotein subfractions (VLDL, IDL, LDL, HDL-L, HDL-M, HDL-D) were isolated by rapid gradient ultracentrifugation using a fixed-angle rotor. The apolipoprotein (by reverse-phase HPLC) and lipid (by enzymatic assays) composition of each subfraction was determined. After three months, there were few group differences. However, the portal group had substantial reductions in VLDL apoB at both six (-50% vs. +1%) and twelve months (-57% vs. +149%, P = .042) while the systemic group had increases in VLDL apoB. Similar differences were seen in IDL apoB (six months: -38% vs. +13%; twelve months: -61% vs. +56%, P = .008). LDL apoB increased in both groups at six months (portal: +7%; systemic: +30%) but fell in the portal group at twelve months (-17% vs. +41%, P = .0007). IDL triglyceride, cholesterol ester, phospholipids, and free cholesterol also fell by 19% to 47% in the portal group while they rose by 8% to 44% in the systemic patients, six and twelve months after surgery (P < .05). In addition, the VLDL and LDL free cholesterol to phospholipid ratios (FC/PL) fell (improved) by 16% to 26% in the portal patients while they rose by 9% to 28% in the systemic subjects during this time (P < .04). Finally, there were substantial improvements in the LDL composition of the portal patients compared to the systemic patients at six (PL/apoB: +23% vs. -16%, P = .005; CE/apoB: +14% vs. -14%, P = .037) and twelve months (PL/apoB: +39% vs. -13%, P = .011; CE/apoB: +41% vs. -15%, P = .011). These data indicate that portal drainage of the transplanted pancreas reduced the number of VLDL, IDL, and LDL particles, reduced the total mass of IDL (by 35%), and normalized the VLDL and LDL particle composition. These improvements were not seen in the patients who received systemic drainage of their pancreas. HDL-M also improved in the portal patients (TG: -29% vs. +12%, P = .025) (PL: +22% vs. -5%, P = .014) (total mass: +16% vs. +0.2%, P = .044) but not in the systemic patients six months after surgery. These results suggest that portal venous drainage of the pancreas leads to greater improvements in the lipoprotein composition of IDDM patients than does systemic drainage.

Simvastatin decreases the hepatic secretion of very‐low‐density lipoprotein apolipoprotein B‐100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications

We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% (P = 0.002), triglycerides by 15% [corrected] (P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% (P = 0.002); high-density lipoprotein cholesterol increased by 17% (P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of 1-[13C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a monoexponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007 mg kg-1 day-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0) mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration (P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased Hepatic Secretion of Very-Low-Density Lipoprotein Apolipoprotein B-100 in Obesity: A Stable Isotope Study

1. We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable-isotope gas chromatography-mass spectrometry method in six obese subjects [three males, three females, age 41.5 +/- 3.4 years (mean +/- SEM), weight 105.0 +/- 4.8 kg, plasma total cholesterol concentration 6.2 +/- 0.4 mmol/l, triacylglycerol 2.8 +/- 0.8 mmol/l, high-density lipoprotein cholesterol 1.0 +/- 0.2 mmol/l] and six lean control subjects (three males, three females, age 41.8 +/- 3.7 years, weight 68.2 +/- 4.9 kg, total cholesterol concentration 4.5 +/- 0.3 mmol/l, triacylglycerol 0.8 +/- 0.2 mmol/l, high-density lipoprotein cholesterol 1.3 +/- 0.1 mmol/l). 2. Plasma total cholesterol, triacylglycerol and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the obese subjects than in control subjects (P = 0.02, P = 0.03, P = 0.04, respectively). VLDL apoB pool size and absolute secretion rate were significantly higher in the obese subjects than in control subjects (323.4 +/- 99.8 mg versus 53.6 +/- 17.1 mg, P = 0.004; and 42.3 +/- 13.8 mg kg fat-free mass-1 day-1 versus 10.7 +/- 0.4 mg kg fat-free mass-1 day-1, P = 0.01), but there was no significant difference in the fractional catabolic rate of VLDL apoB.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in cholesteryl ester storage disease

Using a stable isotope method, we measured the hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in a 26-year-old women who had dyslipidemia due to cholesteryl ester storage disease (CESD) and in five normolipidemic subjects. [1-13C]Leucine was administered by a primed constant intravenous infusion and the enrichment of VLDL apoB was determined by gas chromatography-mass spectrometry. The absolute secretion rate (ASR) of VLDL apoB in the patient was more than twice the mean ASR of the normolipidemic group (17.1 vs 8.0 +/- 0.8 mg/kg body wt. per day). The plasma mevalonic acid concentration, a measure of intrahepatic cholesterol synthesis, was also greater in the patient than in the normolipidemic subjects (8.3 vs 4.4 +/- 1.8 micrograms/L). The findings are consistent with the hypothesis that in CESD increased intrahepatic synthesis of cholesterol stimulates hepatic secretion of VLDL apoB and this may partly account for the dyslipidemia.

Apoprotein B-100 production is decreased in subjects heterozygous for truncations of apoprotein B.

Among individuals who are heterozygous for familial hypobetalipoproteinemia (FHBL) and who have various truncations of apoprotein (apo) B (ie, FHBL with apoB truncation/apoB-100 genotypes), the plasma concentrations of apoB-100 are typically approximately 30% rather than the expected approximately 50% of those in unaffected family members. The metabolic basis for the low apoB-100 levels is unknown. Therefore, we compared the metabolism of apoB-100 in 8 subjects with heterozygous FHBL (2 apoB-89/apoB-100, 2 apoB-75/apoB-100, 2 apoB-54.8/apoB-100, 1 apoB-52/apoB-100, and 1 apoB-31/apoB-100) with the metabolism of apoB-100 in 8 apoB-100/apoB-100 control subjects who were paired with the heterozygotes by gender, age, height, weight, and race. Endogenous labeling of apoB-100 with [13C]leucine and a multicompartmental kinetic model were used to obtain kinetic parameters. FHBL heterozygotes had significantly reduced VLDL apoB-100 production rates (7.7 +/- 3.7 versus 21.2 +/- 6.2 mg.kg-1.d-1, P = .002) and LDL apoB-100 production rates (4.5 +/- 3.12 versus 15.3 +/- 1 mg.kg-1.d-1, P = .05) compared with control subjects. Fractional conversion rates of VLDL to LDL were not significantly different (0.67 +/- 0.36 versus 0.77 +/- 0.17 pools/d), and the respective fractional catabolic rates of apoB-100 in VLDL, IDL, and LDL also were similar in both groups. Thus, FHBL heterozygotes produced apoB-100 at about 30% of the rates of control subjects. We believe these reduced production rates largely account for the lower than expected levels of apoB-100 and LDL cholesterol in the plasma of FHBL heterozygotes.

Effect of Acute Hyperinsulinemia on VLDL Triglyceride and VLDL ApoB Production in Normal Weight and Obese Individuals

Effect of Acute Hyperinsulinemia on VLDL Triglyceride and VLDL ApoB Production in Normal Weight and Obese Individuals

Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals.

The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU.m-2 x min-1) in 17 women (8 chronically hyperinsulinemic obese, BMI = 35.7 kg/m2; 9 normal weight, BMI = 22.5 kg/m2). During acute hyperinsulinemia, plasma FFA decreased by approximately 95% within 1 h in both groups. VLDL triglyceride production decreased 66% in the control subjects (P = 0.0003) and 67% in obese subjects (P = 0.0003). ApoB production decreased 53% in control subjects (P = 0.03) but only 8% in obese (NS). Plasma triglycerides decreased by 40% from baseline in control subjects (P < 0.0001) but only by 10% in obese subjects (P = NS). Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia (P = 0.003). In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably. Acute hyperinsulinemia in humans: 1) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects. Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism.

Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals

Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals

Apolipoprotein metabolism: a stable-isotope approach

Lipids are the major fuel of the body. Efficient functioning as an energy source dictates that lipids must be transportable in the plasma from the point of synthesis and assembly to the storage depots and finally to the tissues to provide energy through oxidative metabolism. Complex lipid forms are transported through the plasma as lipoprotein particles. These particles, secreted from the intestine and liver, have nonpolar outer surface composed of cholesterol, phospholipids, and apolipoproteins. Apolipoproteins are essential for the production, secretion, and continued structural integrity of the various lipoprotein particles and thus play a pivotal role in the control mechanisms of lipid transport. Apolipoproteins regulate specific enzyme activities and modulate plasma lipoprotein clearance through receptor-mediated processes. Quantitative information regarding the rates of synthesis and catabolism of apolipoproteins is vital to an understanding of their metabolism in health and disease. General considerations are followed by a specific use of stable-isotope methodology to quantitative the rate of synthesis of very-low-density-lipoprotein apolipoprotein B-100 (VLDL apo B-100) in control and familial-combined-hyperlipidemic (FCHL) patients.

Diabetes and plasma lipoproteins in Native Americans. Studies of the Pima Indians.

OBJECTIVE--To determine the effects of diabetes on plasma lipoproteins in Pima Indians, to identify metabolic determinants of these differences, and to examine the effects of various modes of diabetes therapy. RESEARCH DESIGN AND METHODS--A series of studies was performed including a population survey of lipoprotein concentrations, kinetic studies of VLDL and LDL metabolism, and studies of the effects of weight loss, sulfonylureas, and high carbohydrate diets. RESULTS--Population data established that diabetes was consistently associated with elevations in total and VLDL TGs and decreases in HDL cholesterol. Metabolic studies indicated multiple alterations in VLDL metabolism induced by NIDDM, including overproduction of VLDL TG, impaired clearance of VLDL TG and apoB, and decreases in adipose tissue lipoprotein lipase. Although changes in LDL concentrations accompanying NIDDM were minimal, the clearance of LDL appeared to be impaired and a higher proportion of VLDL was metabolized without conversion to LDL. There were significant changes in the flux of particles to the LDL compartment. Total and VLDL TG concentrations were found to be inversely related to rates of insulin-mediated glucose disposal, and HDL cholesterol concentrations were positively related to glucose disposal. These relationships between lipoproteins and insulin action were independent of adiposity and insulin, suggesting that insulin resistance may be involved with diabetes-induced changes in VLDL and HDL. Weight loss was associated with decreases in total and VLDL TG, decreases in total and LDL cholesterol, and improvements in the ratio of HDL to LDL cholesterol. Sulfonylurea therapy was associated with lower total and VLDL TGs and lower LDL cholesterol, but little change in HDL. Substitution of complex carbohydrates for saturated fat in the diet showed consistent and significant decreases in total and LDL cholesterol, no decreases in HDL cholesterol, or elevation of total or VLDL TG. CONCLUSIONS--Studies suggest that there are multiple changes in plasma lipoproteins accompanying NIDDM in Pima Indians, but that many of these may be reversed by current modes of hypoglycemic therapy.

Effects of acyl-CoA: Cholesterol O-acyltransferase inhibition on cholesterol absorption and plasma lipoprotein composition in hamsters

1. 1. The ACAT inhibitors, CL 277082 and SA 58-035 were administered for 7 days to hamsters fed diets containing 0.5% cholesterol. 2. 2. Both agents inhibited cholesterol absorption, decreased hepatic, VLDL and IDL cholesterol esters, plasma HDL and HDL apoE and A-I. 3. 3. In addition, CL 277082 treatment produced significant decreases in plasma cholesterol, VLDL apoB and plasma IDL. 4. 4. The cholesteryl esters in VLDL and LDL but not HDL were more polyunsaturated in CL 277082 treated animals. 5. 5. These results support the hypothesis that ACAT inhibition in the cholesterol fed hamster results in an inhibition of dietary cholesterol absorption, thus limiting the cholesterol supply required for the hepatic production of triglyceride-rich lipoproteins.