Very Low Density Lipoprotein Triglyceride Research Articles

Metabolic effects of isradipine as monotherapy or in combination with pindolol during long-term antihypertensive treatment.

To evaluate the effects of isradipine alone and in combination with pindolol on glucose and lipid metabolism during long-term antihypertensive therapy. Open long-term study with parallel groups. Kungsgärdet Geriatric Hospital, Uppsala, a tertiary referral hospital. Twenty-six untreated hypertensive subjects. After 4 weeks on placebo, isradipine was titrated up to 10 mg daily to achieve appropriate blood pressure control (n = 11). If this failed, 5-10 mg pindolol was added. The treatments were continued for 2 years. Blood pressure, lipoprotein measurements, intravenous glucose tolerance test, hyperinsulinaemic euglycaemic clamp, HbA1c, body weight. Treatment with isradipine alone caused a sustained reduction in blood pressure (-22/-10 mm Hg, P < 0.01), but an increase in body weight (+2.2 kg, P < 0.05) and HbA1c (+1.5%; P < 0.001) were also noted. Addition of pindolol resulted in a similar degree of blood pressure reduction and weight gain, whilst HbA1c was less affected (+1.0%; P < 0.05, compared to isradipine alone). Insulin sensitivity became impaired in both groups (-1.2 to -1.5 mg kg-1 min-1; P < 0.01 for M-value at hyperinsulinaemic clamp) but after adjustment for the change in body weight the impairment was only significant (P < 0.01) in the group with combined treatment. The combined treatment also resulted in an increase in very-low-density-lipoprotein (VLDL) triglycerides (+ 0.37 mmol L-1; P < 0.05). The hypotensive effect of isradipine was sustained during long-term use but was associated with weight gain and an impaired glucose control. When isradipine was combined with pindolol there was also a reduction in insulin sensitivity and an increase in VLDL triglycerides, possibly as effects of the beta-adrenergic blockade.

Determinants of LDL subfraction distribution and concentrations in young normolipidemic subjects.

Human low-density lipoproteins (LDLs) comprise a spectrum of particles that vary in size, density, chemical composition, metabolic behavior, and atherogenicity. To identify determinants of this heterogeneity, we measured the percent distribution and plasma concentration of the three major LDL subfractions in 34 young healthy subjects. These parameters were correlated in univariate and multivariate analyses with various body and lifestyle factors; plasma lipids and lipoprotein; and the activities of cholesteryl ester transfer protein, lipoprotein lipase, and hepatic lipase (HL). Women (n = 15) had significantly more large, buoyant LDL (LDL-I; density, 1.025 to 1.034 g/mL) and high-density lipoprotein2 (HDL2) than men (n = 19). Both the percentage and concentration of LDL-I were correlated negatively with very-low-density lipoprotein triglycerides (VLDL-TG) and HL; they were correlated positively with HDL-cholesterol (HDL-C) and HDL2. In addition, percent LDL-I was negatively correlated with plasma triglycerides, VLDL-C, LDL-C, and apo-lipoprotein (apo) B concentrations. The concentrations of intermediate and small, dense LDL (LDL-II and LDL-III; density, 1.034 to 1.044 and 1.044 to 1.060 g/L, respectively) were positively correlated with LDL-C. LDL-III concentrations were also related to plasma cholesterol and apoB concentrations and HL activity. On multivariate analyses, approximately one third of the variability in LDL-I was explained by HL and plasma triglycerides. More than 80% of the variation in LDL-II was accounted for by a model that combined LDL-C and plasma apoB with body mass index and VLDL-TG.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary protein deficiency affects n−3 and n−6 polyunsaturated fatty acids hepatic storage and very low density lipoprotein transport in rats on different diets

Fatty livers and the similarity between the skin lesions in kwashiorkor and those described in experimental essential fatty acid (EFA) deficiency have led to the hypothesis that protein and EFA deficiencies may both occur in chronic malnutrition. The relationship between serum very low density lipoprotein (VLDL) and hepatic lipid composition was studied after 28 d of protein depletion to determine the interactions between dietary protein levels and EFA availability. Rats were fed purified diets containing 20 or 2% casein and 5% fat as either soybean oil rich in EFA, or salmon oil rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, or hydrogenated coconut oil poor in EFA. Animals were divided into six groups, SOC (20% casein + 5% soybean oil), SOd (2% casein + 5% soybean oil), COC (20% casein + 5% hydrogenated coconut oil), COd (2% casein + 5% hydrogenated coconut oil), SAC (20% casein + 5% salmon oil) and SAd (2% casein + 5% salmon oil). After 28 d, liver steatosis and reduced VLDL-phospholipid contents (P < 0.001) were observed in protein-deficient rats. In protein deficiency, triacylglycerol and phospholipid fatty acid compositions in both liver and VLDL showed a decreased polyunsaturated-to-saturated fatty acid ratio. This ratio was higher with the salmon oil diets and lower with the hydrogenated coconut oil diets. Furthermore, independent of the oil in the diet, protein deficiency decreased linoleic and arachidonic acids in VLDL phospholipids. Conversely, despite decreased proportions of EPA at low protein levels, DHA levels remained higher in rats fed salmon oil diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment with a β-blocker with β 2-agonism improves glucose and lipid metabolism in essential hypertension

In a randomized double-blind crossover study in 42 patients with essential hypertension, the metabolic effects of a β-adrenergic blocker with a pronounced β 2-agonistic effect, dilevalol 400 mg × 1, were compared with those of metoprolol succinate 200 mg × 1. The effects on glucose metabolism were evaluated by the hyperinsulinemic euglycemic clamp technique and an intravenous glucose tolerance test (IVGTT). Insulin-mediated glucose disposal (M) and the insulin sensitivity index (M/I) increased by 19% ( P = .011) and 10% ( P = .27), respectively, during dilevalol treatment, but decreased by 10% ( P = .15) and 22% ( P = .0025), respectively, during metoprolol treatment, giving rise to significant differences between the two treatment regimens. Compared with dilevalol-treated patients, those treated with metoprolol showed increased plasma insulin values at the end of the IVGTT, but there was no difference in plasma glucose concentrations or glucose tolerance. Hemoglobin A 1c (HbA 1c) levels increased by 5.4% ( P = .04) in the metoprolol group. Serum cholesterol, total serum and very-low-density lipoprotein (VLDL) triglycerides, and serum urate levels decreased significantly (by 6%, 22%, 29%, and 14%, respectively) during dilevalol treatment, and there was a significant difference between the effects of the two drugs on total, VLDL, and low-density lipoprotein (LDL) triglyceride and serum urate levels. These data demonstrate that a β-blocker with a partial β 2-agonist action differs in its metabolic effect profile from a selective β 1-blocker and may offer advantages by improving glucose and lipid metabolism.

Is there a sex difference in the association of plasma insulin level and insulin sensitivity with serum lipids and lipoproteins?

Previous studies on the relationship between the plasma insulin level, insulin sensitivity (S l), serum lipids, and lipoproteins have been performed predominantly in men. Therefore, we investigated whether there is a sex difference in the association of insulin level during an oral glucose tolerance test and S l with lipids and lipoproteins among normoglycemic men and women aged 53 to 61 years. S l was determined by the minimal model from the frequently sampled intravenous glucose tolerance test (IVGTT). There were no correlations between total cholesterol or low-density lipoprotein (LDL) cholesterol and insulin level or S l. High-density lipoprotein (HDL) cholesterol correlated inversely with fasting insulin ( r = −.26, P < .05 in men; r = −.29, P < .01 in women) and 2-hour insulin ( r = −.31, P < .01 in men; r = −.39, P < .001 in women) and positively with S I ( r = .28, P = .05 in men; r = .43, P < .001 in women). Total and very-low-density lipoprotein (VLDL) triglycerides correlated positively with fasting insulin ( r = .43, P < .001 in men; r = .42, P < .001 in women) and 2-hour insulin ( r = .50, P < .001 in men; r = .31, P < .01 in women) and inversely with ( r = −.49, P < .001 in men; r = −.40, P < .001 in women). In multiple regression analyses including age, body mass index (BMI), waist to hip ratio, 2-hour glucose, fasting or 2-hour insulin, and S I, only BMI was associated with HDL cholesterol level in men. In women, S I was positively associated with HDL cholesterol level independently of obesity and insulin level. Both in men and in women, S I was inversely associated with total and VLDL triglyceride levels independently of obesity and fasting insulin level. In conclusion, a high insulin level and insulin resistance were associated with low HDL cholesterol and high total triglyceride and VLDL triglyceride levels in both men and women. Therefore, it is probable that insulin resistance is related to an excess risk of atherosclerosis also in postmenopausal women, as previously shown in men.

Lipids and Lipoproteins Predicting Coronary Heart Disease Mortality and Morbidity in Patients with Non-Insulin Dependent Diabetes

BACKGROUND The aim of this study was to investigate the association of lipoprotein fractions with the future risk of coronary heart disease (CHD) in patients with non-insulin-dependent diabetes (NIDDM). METHODS AND RESULTS At baseline, lipoprotein fractions were determined in 313 diabetic patients with NIDDM (153 men and 160 women), and these patients were followed up for 7 years with respect to CHD events (CHD death or all CHD events including CHD death or nonfatal myocardial infarction). Altogether, 56 NIDDM patients (28 men and 28 women) died from CHD and 25 had a nonfatal myocardial infarction (17 men and 8 women) during the follow-up. NIDDM patients having these CHD events during the follow-up had higher levels of total and very-low-density lipoprotein (VLDL) triglycerides and VLDL cholesterol and lower levels of high-density lipoprotein (HDL) and HDL2 cholesterol than those without CHD events. The risk for CHD death was fourfold and for all CHD events, twofold higher among diabetics with low HDL cholesterol ( or = 0.9 mmol/L. High triglyceride level (> 2.3 mmol/L) was associated with a twofold increase in the risk of CHD events. In multiple logistic regression analyses, HDL was inversely associated with CHD events and VLDL triglycerides with CHD events in NIDDM patients with low HDL cholesterol level ( CONCLUSIONS Our 7-year follow-up study gives evidence that low HDL and HDL2 cholesterol, high VLDL cholesterol, and high total and VLDL triglycerides are powerful risk indicators for CHD events in patients with NIDDM:

The effect of β,β'-tetramethylhexadecanedioic acid (MEDICA 16) on plasma very-low-density lipoprotein metabolism in rats: role of apolipoprotein C-III

Short term treatment of rats with beta,beta'-tetramethylhexadecanedioic acid (MEDICA 16) results in a pronounced decrease in plasma very-low-density-lipoprotein (VLDL) cholesterol and VLDL triacylglycerol, previously ascribed to a decrease in liver VLDL production [Bar-Tana, Rose-Kahn, Frenkel, Shafer and Fainaru (1988) J. Lipid Res. 29, 431-441]. The hypolipidaemic effect of MEDICA 16 was further analysed here by monitoring plasma VLDL clearance and its hepatic uptake. VLDL triacylglycerol and VLDL apolipoprotein (apo) B fractional clearance rates were increased 7-8-fold in MEDICA 16-treated rats. The increase in the fractional clearance rate of plasma VLDL was essentially eliminated by functional hepatectomy. It was accounted for by activation of plasma VLDL uptake by the liver being completed during the first 4 min after the injection of the VLDL label and before commencement of uptake in non-treated animals. The hypolipidaemic effect of MEDICA 16 was accompanied by a 3.5-fold decrease in plasma apoC-III, but plasma apoC-III clearance remained unaffected by MEDICA 16. MEDICA 16-induced premature hepatic uptake of plasma VLDL due to suppression of apoC-III production may thus account for enhancement of plasma VLDL clearance in treated animals.

Hyperlipidemia in streptozocin-diabetic hamsters as a model for human insulin-deficient diabetes: Comparison to streptozocin-diabetic rats

Characteristics of the lipoprotein profile and metabolism of triglyceride-rich lipoproteins in diabetic hamsters were investigated to assess their suitability as a model for human diabetic hyperlipidemia. Diabetes was induced in the hamsters by intraperitoneal injection of streptozocin (30 mg/kg) for 3 days and compared with the results in streptozocin-diabetic rats (50 mg/kg intravenously). Similar degrees of hyperglycemia and hypoinsulinemia were observed 8 to 10 days after the final streptozocin injection in both groups. Fasting plasma lipid concentrations were about 2.5 times greater in hamsters than in rats. Plasma cholesterol was principally associated with high-density lipoprotein (HDL) in both rodents, although the distribution in very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was significantly greater in hamsters (44%) than in rats (13%). Diabetes increased the concentrations of triglyceride, cholesterol, and phospholipid 5.6- to 7.8-fold in hamsters, whereas it increased them only 1.3- to 1.6-fold in rats. Diabetic hamsters have a plasma lipoprotein profile similar to that of diabetic man, ie, triglyceride-rich lipoproteins are increased and HDL cholesterol is decreased. The concentration of HDL cholesterol was inversely correlated with the severity of hypertriglyceridemia ( r = .76, P < .005). This combination of events does not occur in diabetic rats. Hamsters had a low level of apoprotein B-48-containing triglyceride-rich lipoproteins, although diabetes increased the estimated concentration by fourfold. In rats apoprotein B-48 is the predominant form, but diabetes did not alter the relative proportion of apoprotein B isoforms. The hypertriglyceridemia in both diabetic animals was solely due to a reduction in the clearance of triglyceride-rich lipoproteins, because the output of triglyceride as determined by the Triton WR1339 method was halved and the fractional catabolic rate of radiolabeled VLDL triglyceride was remarkably decreased. Lipoprotein lipase and hepatic lipase activities in postheparin plasma were lower in hamsters than in rats, and diabetes decreased lipoprotein lipase activity by half in hamsters, but not in rats. These results suggest that hamsters may be a more useful model than rats for delineating the disturbance in lipid metabolism that occurs as a result of insulin-deficient diabetes.

Overexpression of human lipoprotein lipase enhances uptake of lipoproteins containing apolipoprotein B-100 in transfected cells.

To investigate the role in lipoprotein metabolism of lipoprotein lipase (LPL) secreted by tissues, we established two cell lines. Fusion plasmids containing either human LPL cDNA or antisense LPL cDNA under control of the cytomegalovirus promoter were transfected into Chinese hamster ovary (CHO) cells, designated as CHO-LPL and CHO-anti-LPL, respectively. CHO-LPL constitutively produced a high level of LPL, whereas CHO-anti-LPL produced a minimal level. When very-low-density lipoprotein (VLDL) was incubated with CHO-LPL, VLDL triglycerides were hydrolyzed, intermediate-density lipoprotein (IDL) was produced, and apolipoprotein E contents increased. CHO-LPL took up and degraded 125I-VLDL at 37 degrees C four times more strongly than did CHO-anti-LPL. Whereas the degradation of apolipoprotein E-deficient VLDL was only 12% that of normal VLDL in CHO-LPL, structural changes of the lipoprotein, including apolipoprotein E expression on the lipoprotein surface, may be important for the cellular uptake of VLDL. Furthermore, we found that binding at 4 degrees C of VLDL and LDL to CHO-LPL was greater than to CHO-anti-LPL, and this binding difference was abolished by washing the cells with heparin. This suggests that cell surface LPL plays a role in the binding of lipoproteins to the cells. We conclude that both the composition of VLDL particles and their cellular binding are influenced by LPL secreted by cells, both of which may enhance the cellular uptake of VLDL.

Hypertriglyceridemia and lowered apolipoprotein C-II/C-III ratio in uremia: Effect of a fibric acid, clinofibrate

We examined the effects of a fibric acid, clinofibrate, on lipoprotein metabolism in 12 hyperlipidemic patients with uremia treated on continuous ambulatory peritoneal dialysis during a 24 week treatment. Daily dose of clinofibrate was 200 mg for the initial four weeks, 400 mg for the second four weeks, and 600 mg for the subsequent 16 weeks. Serum and very-low density lipoprotein (VLDL) triglyceride were decreased by 36% and 48%, respectively. Neither total cholesterol nor apolipoprotein B changed significantly, whereas cholesterol was decreased in VLDL and increased in low (LDL) and high density lipoprotein (HDL) fractions. Post-heparin plasma lipoprotein lipase (LPL) before treatment was not lower than the normal value, and we found no change in LPL activity following clinofibrate. Hepatic triglyceride lipase also did not change. Apolipoprotein (apo) C-II/C-III ratio was low as compared to the normal value before treatment, and the ratio was increased by 38% after the treatment. Decrease in VLDL triglyceride was associated with increase in apo C-II/C-III ratio in all the cases. Abnormal enrichment with triglyceride of LDL and HDL fractions was improved by clinofibrate. Although one patient had a transient and asymptomatic elevation of serum creatine phosphokinase, no patient had muscle pain. There was no accumulation of the drug in the 24 week trial. These results suggest that clinofibrate is an effective and safe approach to the management of dyslipidemia in CAPD patients.

Effects of lovastatin on hepatic fatty acid metabolism.

The in vitro and in vivo effects of lovastatin on fatty acid metabolism were studied in isolated rat hepatocytes. When added in vitro to cell incubations, lovastatin stimulated de novo fatty acid synthesis and acetyl-CoA carboxylase activity, whereas fatty acid synthase activity was unaffected. Lovastatin depressed palmitate, but not octanoate, oxidation. This may be attributed to the lovastatin-induced increase in intracellular malonyl-CoA levels, as no concomitant change of carnitine palmitoyltransferase I (CPT-I) specific activity was detected. Lovastatin had no effect on the synthesis and secretion of triacylglycerols and phospholipids in the form of very low density lipoproteins (VLDL). When rats were fed a diet supplemented with 0.1% (w/w) lovastatin for one week, both acetyl-CoA carboxylase activity and de novo fatty acid synthesis were reduced compared to pair-fed controls, whereas fatty acid synthase activity was unaffected. Palmitate oxidation was enhanced in the lovastatin-fed group. There was an increase in CPT-I activity but no change in intracellular concentration of malonyl-CoA. Lovastatin feeding had no significant effect either on the esterification of exogenous palmitic acid into both cellular and VLDL triacylglycerols and phospholipids or on hepatic lipid accumulation. The in vitro and in vivo effects of lovastatin were not significantly different between periportal and perivenous hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravascular metabolism of different fatty acids during lipid infusion in man

The differential intravascular metabolism of individual fatty acids contained in triacylglycerol-rich particles was studied by infusing 6 normal subjects for 5h with a conventional soy-based emulsion and an experimental olive oil-based emulsion. Both emulsions contained similar amounts of palmitate (11%) and stearate (3–4%) but the former was quite rich in linoleate (54%) and alpha-linolenate (7%), while the latter was rich in oleate (69%). During hydrolysis of circulating triacylglycerols by endothelial lipases, the associated rise of non-esterified fatty acids (FFA) in plasma represents the balance between fatty acid release and tissue uptake. Plasma levels of triacylglycerols and FFA increased about 3 fold and total body fat oxidation was raised to similar values with both emulsions. Fatty acid pattern quickly changed in plasma triacylglycerols to resemble the composition of emulsion particles, with an exception for palmitate which increased markedly more, suggesting a high level of hepatic re-esterification and re-appearance in nascent very low density lipoprotein triglycerides (VLDL-TG) secreted into the circulation. In plasma FFA, stearate and palmitate increased more and alpha-linolenate much less than expected from their content in the emulsion, indicating probably low tissue uptake for the former ones but avid removal for the latter.

Effects of transdermal 17β‐oestradiol combined with oral progestogen on lipids and lipoproteins in hypercholesterolaemic postmenopausal women

The purpose of the study was to evaluate the effect of transdermal 17 beta-oestradiol with oral progestogen on the plasma levels of lipids, lipoproteins and apolipoproteins in hypercholesterolaemic postmenopausal women. During 6 months of replacement therapy with transdermal 17 beta-oestradiol combined with oral progestogen, plasma lipids, lipoproteins and apolipoproteins after 3 and 6 months were measured and compared with pretreatment values by Student's t-test. From January 1992 until September 1992 patients were diagnosed and treated in an out-patient clinic of the Department of Endocrinology Medical Centre for Postgraduate Education, Warsaw. The patients studied were 11 non-obese postmenopausal women with hypercholesterolaemia based on the World Health Organization criteria. Venous blood samples were obtained before and 3 and 6 months after the beginning of cyclic replacement therapy with transdermal 17 beta-oestradiol (E2 100 micrograms day-1 combined with oral chlormadinone acetate (2 mg day-1 for 7 days in each cycle). The antiatherogenic effect of transdermal oestrogen replacement therapy exerted by increased levels of high-density lipoprotein subfraction 2 cholesterol (HDL2-C) leading to the decrease of the total cholesterol level was anticipated. After 6 months of the treatment the concentrations of HDL2 cholesterol (HDL2-C) increased from 0.45 +/- 0.07 mmol l-1 to 0.73 +/- 0.03 mol l-1 (P < 0.05) but the levels of HDL3 cholesterol (HDL3-C) decreased from 1.15 +/- 0.06 mmol l-1 to 0.89 +/- 0.07 mmol l-1 (P < 0.05). The concentrations of total cholesterol decreased from 6.9 +/- 0.13 mmol l-1 to 6.2 +/- 0.2 mmol l-1 (P < 0.05). No changes were observed in the plasma levels of total triglycerides, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglycerides, apolipoproteins A-I and B. In hypercholesterolaemic postmenopausal women, transdermally administered 17 beta-oestradiol 100 micrograms daily in combination with oral chlormadinone acetate has a beneficial effect through raising the level of the antiatherogenic HDL2-C subfraction and decreasing the level of total cholesterol.

Altered Hepatic Production of Apolipoproteins B and E in the Fasted Septic Rat: Factors in the Development of Hypertriglyceridemia

The etiology of hypertriglyceridemia associated with sepsis remains unclear, but we will attempt to elucidate its character by studying the hepatic production of apolipoproteins B and E. Male Lewis rats (260-330 g) were assigned to two groups, control (n = 5) and septic (n = 5). The septic group was injected with 2 × 108 live Escherichia coli colonies/100 g body wt. Food was removed from all rats after injections. Twenty-four hours later a recirculating in situ liver perfusion was performed for 120 min with KRB buffer, containing l -[35S]methionine. The production of apolipoprotein B (apo B), apolipoprotein E (apo E), albumin, and transferrin was determined by immunoprecipitation. The septic rats showed a protein-specific response to sepsis. The total protein secreted increased throughout each perfusion, septic greater than control. Apo B production was increased 2.6-fold in the septic versus control groups (P = 0.037), while apo E production was decreased by 2.9 times control (P = 0.036). Albumin production was decreased 2-fold in the septic group (P = 0.002). The increased hepatic production of apo B represents an increased number of very low density lipoprotein (VLDL) particles and contributes to the elevated VLDL triglyceride levels seen in sepsis. In contrast, decreased apo E production may result in a diminished ability for peripheral and/or hepatic receptor recognition of VLDL and VLDL remnants, respectively. Each of these changes are factors in the development of hypertriglyceridemia in sepsis.

Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes.

The aim of this study was to investigate the association of lipoprotein fractions with the future risk of coronary heart disease (CHD) in patients with non-insulin-dependent diabetes (NIDDM). At baseline, lipoprotein fractions were determined in 313 diabetic patients with NIDDM (153 men and 160 women), and these patients were followed up for 7 years with respect to CHD events (CHD death or all CHD events including CHD death or nonfatal myocardial infarction). Altogether, 56 NIDDM patients (28 men and 28 women) died from CHD and 25 had a nonfatal myocardial infarction (17 men and 8 women) during the follow-up. NIDDM patients having these CHD events during the follow-up had higher levels of total and very-low-density lipoprotein (VLDL) triglycerides and VLDL cholesterol and lower levels of high-density lipoprotein (HDL) and HDL2 cholesterol than those without CHD events. The risk for CHD death was fourfold and for all CHD events, twofold higher among diabetics with low HDL cholesterol (< 0.9 mmol/L) than among diabetics with HDL cholesterol > or = 0.9 mmol/L. High triglyceride level (> 2.3 mmol/L) was associated with a twofold increase in the risk of CHD events. In multiple logistic regression analyses, HDL was inversely associated with CHD events and VLDL triglycerides with CHD events in NIDDM patients with low HDL cholesterol level (< or = 1.12 mmol/L). Our 7-year follow-up study gives evidence that low HDL and HDL2 cholesterol, high VLDL cholesterol, and high total and VLDL triglycerides are powerful risk indicators for CHD events in patients with NIDDM:

The effects of saturated fat and n-6 polyunsaturated fat on postprandial lipemia and hemostatic activity

The effect of different fat loads on postprandial lipemia and hemostatic activity was examined in 10 middle-aged men using 3 different meals. One meal was rich in saturated fatty acids (cream), the other rich in n-6 polyunsaturated fatty acids (sunflower oil) and the third was fat-free containing only carbohydrates. Lipoprotein lipids and hemostatic parameters were measured during fasting and 2, 4, 6 and 8 h after the test meal. In fasting samples, several hemostatic parameters were significantly associated with lipoprotein lipids. Most notable were the strong associations of fibrinolysis parameters tissue plasminogen activator antigen and plasminogen activator inhibitor activity (PAI-1) with total and very low density lipoprotein (VLDL) triglycerides. During lipemia, the associations were approximately similar or slightly weaker than in the fasting state. Both fat loads resulted in similar postprandial lipid responses: VLDL and high density lipoprotein (HDL) triglycerides reached maximum at 4 h after the meal. VLDL cholesterol also increased 4 and 6 h after the fat loads. HDL 3 cholesterol declined after the fatty meals but no change was observed in the HDL 2 fraction. The fat-free meal gave no significant lipid changes during the time course studied. Factor VII activity (F VII;C increased 6 and 8 h after the fatty meals, whereas a decrease was observed after the fat-free meal. The changes (± S.D.) at 8 h after cream, sunflower oil and fat-free meal were 5.2 ± 3.3, 3.3 ± 4.2 and -5.8 ± 7.9 percentage points, respectively, and the effect of the meal on the changes was statistically significant (F (8,99) = 2.99, P = 0.0048). F VII antigen (F VII:Ag) tended to decline during the day but there was no difference between the meals. Factor VIII activity (F VIII:C) was highest after the polyunsaturated fat meal and lowest after the fat-free meal. PAI-1 declined during the day and the decline tended to be steepest after the fat-free morning meal. The effect of the meal on the changes in lipoprotein lipids and hemostatic factors varied significantly between individuals. In conclusion, postprandial lipemia after a single fatty meal was associated with procoagulatory change in F VILC but there was no difference between saturated fat and n-6 polyunsaturated fat.

Differential effects of estrogen on low-density lipoprotein subclasses in healthy postmenopausal women

The use of estrogen by postmenopausal women decreases plasma low-density lipoprotein (LDL) cholesterol levels. To determine whether LDL subclass profiles influence this response, we studied 31 healthy postmenopausal women who were administered two doses (0.625 and 1.25 mg/d) of conjugated equine estrogen in a placebo-controlled double-blind crossover study. Lipid-stained gradient gels were used to categorize LDL subclass patterns. All women were classified as LDL subclass pattern A (predominant LDL peak ≥260 Å). Within the pattern A classification, there were 12 women during placebo treatment with LDL subclass I pattern (predominant LDL peak >271 Å) and 19 women with LDL subclass II pattern (predominant LDL peak ≤ 271 and ≥ 260 Å). Postmenopausal women with LDL subclass I on placebo treatment had significantly lower LDL cholesterol levels compared with women having LDL subclass II (126 ± 28 v 147 ± 23 mg/dL, P < .03). Postmenopausal women with LDL subclass I also had significantly ( P < .05) lower very-low-density lipoprotein (VLDL) cholesterol, VLDL triglyceride, and VLDL apo B levels and significantly higher ( P < .05) high-density lipoprotein 2 (HDL 2) cholesterol, HDL 3 cholesterol, and HDL 2 apo A-I levels. Estrogen replacement significantly ( P < .05) decreased LDL cholesterol levels and increased VLDL and LDL triglyceride, HDL 2 and HDL 3 cholesterol and apo A-I, and HDL 2 apo A-II levels to a similar extent in postmenopausal women with LDL I or II subclass patterns. Estrogen replacement at either dose in postmenopausal women with the LDL I subclass pattern decreased LDL I relative peak area and LDL II peak particle diameter from 55% ± 1.7% to 39% ± 2.3% (mean ± SEM, P < .001) and from 269 ± 0.5 to 267 ± 0.7 Å (mean ± SEM, P < .001), respectively. In postmenopausal women with the LDL II subclass pattern, no significant change in LDL subclass distribution or peak diameter was noted. The prevalence of pattern B (predominant LDL peak <260 Å) and the mean proportion of LDL subclass III particles (<260 Å, 12%) were unaffected by estrogen treatment. In summary, estrogen replacement therapy decreased the proportion of large LDL I particles and increased the proportion of intermediate-size LDL II particles in healthy postmenopausal women with a predominance of large LDL particles at baseline. However, estrogen treatment did not increase the proportion of small, dense LDL III particles or result in conversion to LDL pattern B, attributes of LDL that have been associated with increased coronary artery disease risk in men.

Unsaturated fatty acid bioavailability in growing rats fed low or adequate protein diets with sunflower or soybean oils

The relationship of serum very low density lipoproteins (VLDL) to hepatic lipid composition was studied after 28 days of protein depletion to determine the interactions between dietary protein levels and the essential fatty acid (EFA) availability. This was examined in rats using a dietary combination of 20% or 2% casein with 5% vegetable oils, variable in their n-6:n-3 fatty acid ratios. Rats were divided into four groups, SFC (20% casein + 5% sunflower oil); SFd (2% casein + 5% sunflower oil); SC (20% casein + 5% soybean oil); Sd (2% casein + 5% soybean oil). Dietary protein depletion decreased phospholipid and protein concentrations in liver and VLDL, whereas triacylglycerol amounts were enhanced in liver, but lowered in VLDL. Dietary protein depletion strongly depressed VLDL apolipoproteins. Protein-deficient groups (SFd and Sd) exhibited, in both liver and VLDL, decreased linoleic acid in triacylglycerol fractions and depressed both arachidonic and linoleic acids in phospholipid fractions. In spite of short periods of dietary treatment, protein depletion involved an impairment in EFA availability. Total n-6 polyunsaturated fatty acids contents were diminished in liver and VLDL lipids, while total n-3 polyunsaturated fatty acids contents were diminished in only VLDL triacylglycerol and phospholipid. Furthermore, sunflower oil amplified this impairment, and the lack of α-linolenic acid involved a greater diminution in n-3 polyunsaturated fatty acids and enhanced 20:3 n-9 and 22:5 n-6, especially in phospholipid fractions. In this experiment, in spite of a short period of dietary treatment, protein depletion strongly impairs EFA metabolism and accentuates the α-linolenic acid deficiency.

Evidence that cholesteryl ester and triglyceride accumulation in J774 macrophages induced by very low density lipoprotein subfractions occurs by different mechanisms

The present investigations have examined the mechanism(s) whereby Sf 60-400 very low density lipoproteins (VLDL) from Type IV hypertriglyceridemic subjects cause cholesteryl ester and triglyceride accumulation in J774 macrophages. Both apolipoprotein (apo) E-poor and apoE-rich Type IV VLDL subfractions, isolated by heparin-Sepharose chromatography, were capable of enhancing cellular cholesterol and triglyceride content. The apoE-rich fraction was significantly more effective at inducing cholesterol esterification (P < 0.05) and accumulation of esterified cholesterol (P < 0.05), whereas both subfractions caused similar increases in cellular triglyceride content. Thus, the amount of VLDL-associated apoE determined the extent to which Type IV VLDL loaded J774 cells with cholesterol but not triglyceride. Two VLDL subfractions, Sf 60-400 and Sf 20-60, isolated from Type III subjects homozygous for apoE2, caused little or no effect on cellular esterified cholesterol content, whereas both fractions induced the same degree of cellular triglyceride accumulation as Type IV VLDL. Type IV VLDL-induced cholesteryl ester accumulation was blocked by an anti-apoE monoclonal antibody, known to block the binding of apoE to the LDL receptor; however, the increase in cellular triglyceride was unaffected. Therefore, VLDL-induced triglyceride accumulation in this cell line can occur without apoE-mediated uptake of intact VLDL particles. The addition of heparin to J774 cells resulted in a 6-fold increase in lipoprotein lipase (LPL) activity in the media, and significantly enhanced the ability of Type IV VLDL to induce cellular triglyceride accumulation (P < 0.01), but significantly decreased cellular cholesteryl ester content (P < 0.025). Finally, Sf 60-400 VLDL from two subjects homozygous for apoC-II deficiency failed to increase cellular lipid content. However, the addition of exogenous apoC-II to C-II-deficient VLDL resulted in significant increases of both triglyceride and esterified cholesterol in J774 cells. In the presence of apoC-II, the anti-apoE monoclonal antibody blocked the cellular cholesteryl ester increase induced by C-II-deficient VLDL, but had no effect on the increase in cellular triglyceride. Collectively, these experiments demonstrate that extracellular lipolysis of Sf 60-400 VLDL by LPL is required for cholesteryl ester and triglyceride accumulation in J774 macrophages. After interaction with cellular LPL, VLDL triglycerides are hydrolyzed. The resulting free fatty acids are readily taken up by the macrophage, and re-esterified into triglyceride. Lipolysis proceeds until apoE epitopes are exposed, allowing the triglyceride-depleted remnant, containing all the cholesteryl ester, to be taken up via an apoE-mediated process.

Cholesterol feeding induces hypertriglyceridaemia in hamsters and increases the activity of the Mg 2+-dependent phosphatidate phosphohydrolase in the liver

(1) Feeding increased cholesterol to hamsters resulted in a dose-dependent increase in cholesterol and triacylglycerol in very-low-density lipoprotein (VLDL), in serum non-esterified fatty acids and in the activity of the Mg 2+-dependent phosphatidate phosphohydrolase in liver. (2) The effects of increasing dietary cholesterol by 0.12% (w/w) in addition to feeding fat (14%, w/w) were dependent upon the nature of the fat. Lard in the presence of 0.12% (w/w) cholesterol increased serum triacylglycerols as did olive oil. By contrast, sunflower oil did not cause a significant change in serum triacylglycerol concentrations. (3) There was a highly positive correlation between VLDL triacylglycerol and VLDL cholesterol concentrations suggesting that, at least in this model, there is a close relationship between hypertriglyceridaemia and hypercholesterolaemia.