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PubMed1989

Impaired triacylglycerol catabolism in hypertriglyceridemia of the diabetic, cholesterol-fed rabbit: a possible mechanism for protection from atherosclerosis.

The etiology of the hypertriglyceridemia in alloxan-diabetic rabbits was studied by two independent methods. Production and removal rates of VLDL triacylglycerol were measured in diabetic rabbits by injection of [3H]palmitate-labelled VLDL. Similarly, triacylglycerol total removal rates were determined in non-diabetic rabbits which were infused with Intralipid to mimic the plasma triacylglycerol concentrations of diabetic rabbits. Compared to nondiabetic rabbits, triacylglycerol removal rats were decreased in diabetic rabbits, particularly at higher levels of plasma triacylglycerol. During cholesterol and triacylglycerol supplementation of the diet, post-heparin plasma lipoprotein lipase activity of diabetic rabbits with severe hypertriglyceridemia averaged 36% of that of nondiabetics, suggesting an impaired triacylglycerol removal capacity. Furthermore, plasma triacylglycerol was inversely related to post-heparin plasma lipoprotein lipase activity among diabetic rabbits. VLDL triacylglycerol production increased with increasing plasma triacylglycerol concentration among diabetic cholesterol-fed rabbits with moderately severe hypertriglyceridemia, but reached an apparent plateau among rabbits with plasma triacylglycerol concentrations from approx. 2000-9000 mg/dl. Thus, severe hypertriglyceridemia in this model of insulin deficiency can be attributed only partially to VLDL hypersecretion, whereas a removal defect, resulting in saturation of the triacylglycerol removal mechanism, appears to be largely responsible. The impaired removal of plasma triacylglycerol is also related to the presence of cholesterol predominantly in lipoproteins of increased size. The data support the hypothesis that protection against atherosclerosis in cholesterol-fed diabetic rabbits results from exclusion of very large cholesterol-containing lipoproteins from the arterial wall.

Animals↗
PubMed1993

Lipoprotein lipase mass and activity in severe hypertriglyceridemia.

To clarify the role of defective lipoprotein lipase (LPL) in hypertriglyceridemia, the LPL masses and LPL activities in post-heparin plasma (PHP) were studied in severe hypertriglyceridemias. The developed sandwich enzyme immunoassay for the LPL was sensitive from 0.5 to 20 ng/ml of LPL in human PHP. The plasma LPL mass increased by heparin injection (30 USP units/kg) and was found to positively correlate with LPL activity. The mean LPL activity from PHP of normal controls was 2,960 +/- 1,057 nmol/ml/h. The mean LPL masses from human pre- and 15-min post-heparin plasma from normal subjects were 25 +/- 5 ng/ml and 224 +/- 60 ng/ml, respectively. Thus the specific activity of LPL from PHP of normal controls was calculated to be 13.3 mumol FFA released/h/microgram LPL. Among hypertriglyceridemic patients with over 1,000 mg/dl of serum triglyceride, the incidence of patients with LPL masses less than -2 standard deviations (S.D.) of those of average normal control subjects was found to be 27%. Seventy percent of patients showed specific activities within + 2 S.D. of those of average control LPL, and 30% showed significantly low specific activities less than -2 S.D. despite the fact that LPL masses were not less than -2 S.D. of the average normal controls. These results suggest that the evaluation of LPL masses in PHP would be useful for finding functionally defective LPL in patients with hypertriglyceridemia, and that up to 30% severe hypertriglyceridemias may have functionally defective LPL.

Adult↗
PubMed1991

Low superoxide scavenging activity associated with enhanced superoxide generation by monocytes from male hypertriglyceridemia with and without diabetes.

To investigate the mechanism of increased superoxide (O2-) generation by monocytes from patients with hypertriglyceridemia, superoxide scavenging activity (SSA) and O2- generation by monocytes were determined concomitantly employing an electron spin resonance/spin trapping method and 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo [1,2-a]-pyrazin-3-one (MCLA)-dependent chemiluminescence, respectively. Peripheral monocytes were separated by the adherent methods from the following four male groups: normal control, diabetes alone (DM), diabetes with hypertriglyceridemia (DM + HTG) and hypertriglyceridemia alone (HTG). Monocytes were stimulated by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) or opsonized zymosan (OZ). O2- generation by monocytes upon stimulation was enhanced in HTG and HTG + DM but not in DM as compared to that in normal controls. The mean value of SSA in monocytes was similar among the 4 groups. When the relationship was analyzed using various parameters, a significant positive relationship was found between O2- generation and the plasma triglyceride level; a significant negative correlation was found between SSA and both the O2- generation and the plasma triglyceride level. In the in vitro system, the SSA in monocytes decreased significantly after the the stimulation by either of PMA or OZ. The results indicate that the decrease of SSA in monocytes may originate from the enhanced in vivo O2- generation and is responsible for the enhanced O2- release against the stimuli in hypertriglyceridemia. These abnormal functions of monocytes may in part accelerate the development of atherosclerosis.

Adult↗
PubMed1994

Lipoprotein(a) concentrations and phenotypes in controls and patients with hypercholesterolemia or hypertriglyceridemia.

Lipoprotein(a) [Lp(a)] concentrations are known to be stable under various dietary and drug regimens. Little is known about the influence of hyperlipoproteinemia on Lp(a) levels. Therefore, we investigated Lp(a) concentrations and apolipoprotein(a) [apo(a)] polymorphism in 147 patients with hypertriglyceridemia and in 93 patients with hypercholesterolemia and compared them with 404 subjects without hyperlipoproteinemia (controls). Despite a similar apo(a) isoform and phenotype distribution, Lp(a) concentrations differed significantly (P < .0001) between the three groups. The median Lp(a) level in control subjects was 17 mg/dL (mean, 38 mg/dL), compared with 38 mg/dL (mean, 56 mg/dL) in patients with hypercholesterolemia and 9 mg/dL (mean, 21 mg/dL) in those with hypertriglyceridemia. These differences persisted after exclusion of 61 subjects with coronary heart disease. The inverse correlation between the molecular weight of the apo(a) isoforms and the Lp(a) concentration was preserved within each group (P < .001), but for every molecular weight range studied the level of Lp(a) was always higher in patients with hypercholesterolemia and always lower in those with hypertriglyceridemia than in controls. We conclude that hypertriglyceridemia or hypercholesterolemia have profound--but divergent--influences on the concentration of Lp(a).

Female↗
PubMedDate not supplied

Paraoxonase 1 and platelet-activating factor acetylhydrolase activities in patients with low hdl-cholesterol levels with or without primary hypertriglyceridemia.

BACKGROUND: Previous studies have shown that high density lipoprotein (HDL)-deficient states are associated with reduced paraoxonase 1 (PON1) activity. However, HDL reduction caused by primary hypertriglyceridemia has not been fully explored. The aim of the present study was to evaluate whether PON1 and platelet-activating factor acetylhydrolase (PAF-AH), two antioxidant enzymes, were altered in patients with low HDL-cholesterol levels with or without primary hypertriglyceridemia in comparison with control normolipemic subjects. METHODS: We studied 24 patients with low HDL-cholesterol levels with (n=12) or without (n=12) primary hypertriglyceridemia in comparison with 12 control subjects who presented normal HDL-cholesterol and triglyceride levels. Paraoxon and phenylacetate were used as substrate for measuring PON1 activities and 1-hexadecyl-2-[3H]acetyl-glycero-3-phosphocholine for platelet-activating factor acetylhydrolase (PAF-AH) activity. Double substrate method was used to assign phenotypes. Lipid, lipoprotein, apolipoprotein, and lipoprotein particles were determined by standardized methods. RESULTS: Both PON1 activities were significantly reduced in patients with low HDL-cholesterol levels. This reduction could be selectively attributed to the hypertriglyceridemic subgroup. PAF-AH activity was not different between hypoalphalipoproteinemic patients and controls. PON1 activities correlated positively and significantly with HDL-cholesterol, HDL2-cholesterol, HDL3-cholesterol, HDL-phospholipids, apo A-I, apo A-II, and LpA-I:A-II. PAF-AH correlated positively and significantly with total and low density lipoprotein-cholesterol. CONCLUSIONS: Data from this study would suggest that in hypoalphalipoproteinemic syndrome, particularly when associated with hypertriglyceridemia, there is impairment in enzymatic antioxidant activity exclusively related with HDL.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2005

Glucose-stimulated insulin response in non-diabetic patients with lipoprotein lipase deficiency and hypertriglyceridemia.

Elevations in plasma triglyceride (TG) and free fatty acid (FFA) concentrations are generally thought to play a role in the pathogenesis of insulin-resistant diabetes. The objective of this study was to investigate the relationship between hypertriglyceridemia and glucose-stimulated insulin responsiveness in non-diabetic patients. Forty subjects were divided into three BMI-matched groups as follows: one group consisted of 8 patients with a lipoprotein lipase (LPL) deficiency, another consisted of 12 patients with hypertriglyceridemia and a third consisted of 20 subjects with normal TG levels. In response to a 75 g oral glucose tolerance test, plasma insulin levels in the LPL-deficient subjects were higher (106+/-11 microU/ml) than those in the hypertriglyceridemic (69+/-16 microU/ml) and normolipidemic (29+/-3 microU/ml) subjects, at 30 min. On the other hand, their plasma glucose levels (127+/-6 mg/dl) were less than those seen in the normolipidemic group (165+/-9 mg/dl) after 90 min. Thus, LPL-deficient subjects with hypertriglyceridemia displayed an enhanced glucose-stimulated insulin response as well as lower blood glucose levels, the latter of which is not generally seen in those with hypertriglyceridemia and normolipidemia.

Adult↗
PubMed2004

Chronic hypertriglyceridemia in young watanabe heritable hyperlipidemic rabbits impairs endothelial and medial smooth muscle function.

Several studies have suggested that hypertriglyceridemia is a common risk factor for coronary heart disease. Although increasing serum levels of triglyceride correlate with hypercoagulability, little is known about the contribution of hypertriglyceridemia to vascular function. We successfully segregated two lines of rabbits with genetically-determined severely high (TGH; 2764 +/- 413 mg/dl) and moderately high (TGL; 191 +/- 12 mg/dl) levels of triglyceride, but with comparable levels of total cholesterol, from Watanabe heritable hyperlipidemic rabbits. To determine whether hypertriglyceridemia was involved in alterations of vascular function, we conducted isometric tension studies and analyzed protein expression on thoracic aortic rings isolated from young (3-4 month) TGH, TGL and Japanese White rabbit (JW). No difference in percentage of plaque area in the thoracic aorta was found between TGH and TGL. Relaxing responses, evoked by sodium nitroprusside were similar in JW, TGL and TGH, but endothelium-dependent relaxation to acetylcholine was impaired in TGH compared with JW or TGL (maximal relaxation in JW; 83.5 +/- 2.7%, TGL; 79.9 +/- 5.3%, TGH; 59.1 +/- 5.7%, p<0.05). Relaxation to A23187 was also attenuated in TGH compared with JW, but not significantly different between TGL and JW. Endothelium-independent relaxation elicited by isoproterenol in TGH was significantly decreased compared with JW or TGL (maximal relaxation in JW; 95.2 +/- 2.6% TGL; 91.0 +/- 4.9%, TGH; 75.1 +/- 5.2%, p<0.05). Protein expression of angiotensin II type-1 receptor was increased in TGH and that of nitric oxide synthases-3 was attenuated in TGH compared with TGL. This is the first study showing that endothelium-dependent and -independent vascular relaxation under the condition of combined hyperlipidemia was severely impaired as compared to that under only hypercholesterolemia. These results suggest that hypertriglyceridemia aggravates functional impairment induced by hypercholesterolemia in endothelial and smooth muscle cells.

Animals↗
PubMed2006

Plasma exchange in severe hypertriglyceridemia a clinical study.

BACKGROUND: Hypercholesterolemia and hypertriglyceridemia are independent risk factors for atherosclerotic heart diseases. Moreover acute pancreatitis may occur in patients with severe hypertriglyceridemia. AIM OF THE STUDY: To evaluate the effectiveness of plasma exchange (PE) in patients with severe hypertriglyceridemia. METHODS: Seven patients with severe hypertriglyceridemia (a triglyceride level of more than 1000mg/dl) were treated with PE. After PE, lipid and hematological parameters and side effects were evaluated. RESULTS: Triglyceride levels decreased below 1000mg/dl in all patients. The levels of triglyceride and very low-density lipoprotein cholesterol (p<0.05 for both), and total cholesterol (p<0.005) decreased significantly. PE was well-tolerated. Liver and renal functions, hematological parameters, except for an increase in white blood cell counts, did not change significantly. CONCLUSION: PE may be used safely and effectively in severe hyperlipidemic patients at risk of acute coronary events and acute pancreatitis. Further extended studies may provide more detailed information.

Humans↗
PubMed2002

Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial.

PURPOSE: To determine whether hypertriglyceridemia is associated with systemic inflammation, which may contribute to the increased cardiovascular risk in patients who have hypertriglyceridemia. In addition, we investigated whether fibrates reverse this inflammatory state. PATIENTS AND METHODS: Serum lipid levels, body mass index, insulin resistance, and inflammatory parameters were compared between 18 patients who had severe hypertriglyceridemia without cardiovascular disease and 20 normolipidemic controls. We measured the ex vivo production capacity of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 after whole-blood stimulation with lipopolysaccharide, as well as circulating levels of C-reactive protein and fibrinogen. A randomized controlled trial was conducted to determine whether bezafibrate (400 mg administered daily for 6 weeks) affected these parameters in hypertriglyceridemic patients. RESULTS: When compared with normolipidemic controls, hypertriglyceridemic patients had significantly lower high-density lipoprotein (HDL) cholesterol and higher triglyceride levels, body mass index, and insulin resistance. In addition, hypertriglyceridemic patients had a significantly higher production capacity of TNF-alpha (mean difference, 11 700 pg/mL; 95% confidence interval [CI]: 7800 to 15,700 pg/mL]) and IL-6 (mean difference, 20,400 pg/mL; 95% CI: 7800 to 32,900 pg/mL), and higher levels of C-reactive protein (mean difference, 0.8 mg/L; 95% CI: 0.1 to 2.4 mg/L) and fibrinogen (mean difference, 0.8 g/dL; 95% CI: 0.3 to 1.3 g/dL). Bezafibrate therapy significantly increased HDL cholesterol levels, reduced triglyceride and insulin resistance levels, and reduced production capacity of TNF-alpha and IL-6, as well as levels of C-reactive protein and fibrinogen. CONCLUSION: Systemic inflammation is present in patients who have the clinical phenotype that is associated with severe hypertriglyceridemia, and may contribute to the increased risk of cardiovascular disease in these patients. Bezafibrate has anti-inflammatory effects in these patients.

Bezafibrate↗
PubMed1998

A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group.

BACKGROUND: To assess the lipid-lowering effects and safety of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. METHODS: We performed a randomized, open-label, parallel-design, active-controlled, study in eight centers in the United States. We enrolled 108 patients with total cholesterol (TC) of > or =200 mg/dL, serum triglycerides (TG) > or =200 and < or =800 mg/dL, and apolipoprotein B (apo B) > or =110 mg/dL. Patients were randomly assigned to receive atorvastatin 10 mg once daily (n=55) or immediate-release niacin 1 g three times daily for 12 weeks (n=53). Patients were stratified based on low-density lipoprotein cholesterol (LDL-C): Patients with LDL-C > or =135 mg/dL were considered to have combined hyperlipidemia and patients with LDL-C <135 mg/dL were considered to have isolated hypertriglyceridemia. The primary outcome measure was percent change from baseline in LDL-C. Other lipid levels were evaluated as secondary parameters. RESULTS: Atorvastatin reduced LDL-C 30% and TC 26% from baseline, and increased high-density lipoprotein cholesterol (HDL-C) 4%. Total TG were reduced 17%. Niacin reduced LDL-C 2%, TC 7%, increased HDL-C 25%, and reduced total TG 29% from baseline. There was a significant difference in LDL-C reduction, the primary efficacy parameter, between the two treatment groups (P <0.05, favoring atorvastatin), as well as a significant difference in the improvement in HDL-C (P <0.05, favoring niacin). The effect of atorvastatin was relatively consistent between patients with combined hyperlipidemia and isolated hypertriglyceridemia, whereas there was more variability between these strata in the niacin treatment group. Atorvastatin was better tolerated than niacin. CONCLUSION: Atorvastatin may allow patients with combined hyperlipidemia to be treated with monotherapy and offers an efficacious and well-tolerated alternative to niacin for the treatment of patients with isolated hypertriglyceridemia.

Adult↗
PubMed2000

Activated platelets in patients with severe hypertriglyceridemia: effects of triglyceride-lowering therapy.

Hypertriglyceridemia, a risk factor for cardiovascular disease, has been associated with hypercoagulability, but whether platelet activation is implicated is unknown. This study was designed to compare the in vivo platelet activation status between patients with severe hypertriglyceridemia and age- and sex-matched control subjects, and to evaluate the effects of triglyceride-lowering therapy. Sixteen patients with primary hypertriglyceridemia were included in a double-blind, placebo-controlled cross-over trial with 400 mg bezafibrate once daily. Platelet activation was analysed by double label flow cytometry, using monoclonal antibodies against GP53, P-selectin, and platelet-bound fibrinogen. Surface expression of the lysosomal membrane protein GP53 was significantly higher in the hypertriglyceridemic patients at baseline as compared to the group of age- and sex-matched controls (16.3+/-4.8% vs. 8.9+/-3.4%, respectively, P<0.001). No differences in the expression of P-selectin and fibrinogen binding were observed. In response to bezafibrate therapy, the expression of GP53 in the patient group decreased from 16.3+/-4.8% to 13.1+/-4.1% (P=0.018). The expression of P-selectin and fibrinogen binding was not affected by bezafibrate therapy. In conclusion, patients with hypertriglyceridemia have an increased in vivo platelet activation status, which can be improved by bezafibrate therapy.

Antigens, CD↗
PubMed2001

No Influence of acute hypertriglyceridemia on plasma t-PA in healthy male volunteers.

Dietary effects on liver blood flow may have biased the previously observed effects of hypertriglyceridemia on systemic tissue-type plasminogen activator (t-PA) concentrations. Therefore, in this study the effects of hypertriglyceridemia on plasma t-PA were determined by inducing hypertriglyceridemia with an intravenous fat emulsion (Intralipid) infusion. In a randomised crossover fashion, eight healthy male volunteers received Intralipid 10% (1.5 ml/min) or 0.9% saline for 2 h and 45 min. After 2 h of infusion, t-PA antigen, t-PA activity, t-PA/plasminogen activator inhibitor (PAI-1) complex, and PAI-1 activity were determined. Concomitantly, the effects of Intralipid t-PA clearance were determined from steady-state t-PA antigen concentrations of a 45-min recombinant tissue-type plasminogen activator (rt-PA) infusion (31.25 microg/min). Liver blood flow was assessed from steady-state concentrations of a continuous sorbitol infusion. Differences between treatments were calculated using the prevalue as the covariate. No significant differences were observed in mean+/-S.D. endogenous concentrations of t-PA antigen, 4.5+/-0.9/4.1+/-0.9 ng/ml (Intralipid vs. saline infusion; difference of 0.3 ng/ml, 95% confidence interval, CI: -0.2, 0.8); t-PA activity, 0.69+/-0.21/0.68+/-0.21 U/ml (difference of 0.04 U/ml, CI: -0.17, 0.25); t-PA/PAI-1 complex, 2.0+/-1.3/1.6+/-1.0 ng/ml (difference of 0.1 ng/ml, CI: -0.8, 0.6); and PAI-1 activity, 7.3+/-5.1/7.1+/-5.1 U/ml (difference of 0.26 U/ml, CI: -3.7, 4.3). Mean t-PA clearance and liver blood flow were unaffected by the Intralipid infusion. These results indicate that acute hypertriglyceridemia does not alter plasma fibrinolytic parameters in healthy male volunteers.

Acute Disease↗
PubMed1997

Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity.

OBJECTIVES: We sought to determine whether hypertriglyceridemia in patients with lipoprotein lipase (LPL) dysfunction is associated with endothelial dysfunction in resistance vessels of the forearm vasculature. BACKGROUND: Vasodilator responses to acetylcholine, acting through stimulation of nitric oxide (NO) release from the endothelium, are impaired in hypercholesterolemia and normalized by L-arginine, suggesting dysfunction of the L-arginine/NO pathway. Similar abnormalities have been reported in conditions associated with hypertriglyceridemia, such as non-insulin-dependent diabetes. The relation between endothelial function and plasma triglyceride concentrations has, however, not previously been studied in vivo. METHODS: We examined forearm blood flow responses to brachial artery infusions of acetylcholine (alone and with L-arginine) and nitroprusside (an NO donor) in 17 patients with severe hypertriglyceridemia (mean [+/- SD] plasma triglyceride concentration 1,914 +/- 1,288 mg/dl) but normal low density lipoprotein cholesterol (89 +/- 31 mg/dl) and in 34 normolipidemic control subjects. Severe LPL dysfunction was demonstrated in 10 of 17 patients. RESULTS: Acetylcholine (7.5 and 15 microg/min) produced similar forearm blood flow responses in hypertriglyceridemic patients (mean [+/- SEM] 7.7 +/- 0.9 and 10.5 +/- 1.2 ml/min per 100 ml) and in control subjects (7.5 +/- 0.6 and 11.0 +/- 0.8 ml/min per 100 ml, p = 0.78 by analysis of variance). Responses to acetylcholine co-infused with L-arginine (10 mg/min) and nitroprusside (3 and 10 microg/min) were also similar in hypertriglyceridemic patients and control subjects (p = 0.93 and p = 0.27 for acetylcholine with L-arginine and nitroprusside, respectively). The ratio response to acetylcholine/response to nitroprusside differed between hypertriglyceridemic patients and control subjects by only 1%. The study had >90% power (alpha = 0.05) to detect a difference >30% in this ratio. CONCLUSIONS: Severe hypertriglyceridemia associated with LPL dysfunction is not associated with the degree of endothelial dysfunction seen in moderate hypercholesterolemia when responses to acetylcholine are impaired by >40%.

Acetylcholine↗
PubMed2003

Charge-based heterogeneity of human plasma lipoproteins at hypertriglyceridemia: capillary isotachophoresis study.

To reveal the metabolic links between and within pools of pro-atherogenic triglyceride(TG)-rich lipoproteins and anti-atherogenic high density lipoproteins (HDL), the changes in lipoprotein profile at hypertriglyceridemia were analyzed by capillary isotachophoresis. Plasma samples from patients with apoE3/3 phenotype were stained with a fluorescent probe NBD-C6-ceramide and lipoproteins resolved into six H-, one (V+I) and four L-components which belong to HDL, very low and intermediate density (VLDL+IDL) and low density lipoproteins (LDL), respectively. The expected correlation between the relative size of the combined fractions and lipid and apolipoprotein values was obtained confirming the validity of the approach. The new findings were obtained as follows. (1) The fast L-component correlated inversely with HDL-cholesterol (Chol), while intermediate and slow H-components correlated inversely with plasma and LDL-Chol and apoB. (2) The content of intermediate and slow H-components increased within H-pool and decreased relative TG-rich lipoproteins as hypertriglyceridemia rose due to the impairment of triglyceride hydrolysis by lipoprotein lipase within TG-rich particles. (3) A predictive value of the ratios of fast to slow H-components as an indicator of lecithin:cholesterol acyltransferase activity was demonstrated which tended to decrease at hypertriglyceridemia. (4) The L1/L2 ratio may be considered as an indicator of the accumulation of small dense LDL, which is a feature of clinically manifested atherogenic B-pattern. The competition between H(DL) and L(DL) particles for hepatic lipase and significant contribution of apoE to functional deficiency of H(DL) particles at hypertriglyceridemia are suggested.

Apolipoproteins E↗
PubMed2004

Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice.

Hypertriglyceridemia is a common pathological condition in humans of mostly unknown etiology. Here we report induction of dyslipidemia characterized by severe hypertriglyceridemia as a result of point mutations in human apolipoprotein A-I (apoA-I). Adenovirus-mediated gene transfer in apoA-I-deficient (apoA-I(-)(/)(-)) mice showed that mice expressing an apoA-I[E110A/E111A] mutant had comparable hepatic mRNA levels with WT controls but greatly increased plasma triglyceride and elevated plasma cholesterol levels. In addition, they had decreased apoE and apoCII levels and increased apoB48 levels in very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL). Fast protein liquid chromatography (FPLC) analysis of plasma showed that most of cholesterol and approximately 15% of the mutant apoA-I were distributed in the VLDL and IDL regions and all the triglycerides in the VLDL region. Hypertriglyceridemia was corrected by coinfection of mice with recombinant adenoviruses expressing the mutant apoA-I and human lipoprotein lipase. Physicochemical studies indicated that the apoA-I mutation decreased the alpha-helical content, the stability, and the unfolding cooperativity of both lipid-free and lipid-bound apoA-I. In vitro functional analyses showed that reconstituted HDL (rHDL) particles containing the mutant apoA-I had 53% of scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux capacity and 37% capacity to activate lecithin:cholesterol acyltransferase (LCAT) as compared to the WT control. The mutant lipid-free apoA-I had normal capacity to promote ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. The findings indicate that subtle structural alterations in apoA-I may alter the stability and functions of apoA-I and high-density lipoprotein (HDL) and may cause hypertriglyceridemia.

ATP Binding Cassette Transporter 1↗
PubMed1999

Dietary counselling effectively improves lipid levels in patients with endogenous hypertriglyceridemia: emphasis on weight reduction and alcohol limitation.

OBJECTIVE: To evaluate the short-term effect of dietary counselling in patients with endogenous hypertriglyceridemia and evaluate the effects of advised nutrient changes. DESIGN: A prospective dietary intervention study in patients with endogenous hypertriglyceridemia from January I st 1988 to December 31 st 1996 according to the Dutch guidelines for a healthy diet. Before and after the dietary intervention period of 12 weeks, 24h food recalls were used to assess dietary intake and macronutrient composition. Effectiveness was evaluated by assessment of body weight, serum lipids, lipoproteins and insulin resistance parameters. SETTING: Leiden outpatient Lipid Clinic. SUBJECTS: Forty-five newly diagnosed, untreated patients with endogenous hypertriglyceridemia. RESULTS: A significant reduction in energy intake and body weight as well as changes in macronutrient composition were observed. Total serum triacylglycerol and cholesterol levels decreased by 31% and 15%, respectively. No effects were observed on serum glucose and insulin levels. Weight reduction was significantly correlated with reduction of total plasma triacylglycerol levels and inversely correlated with changes in HDL cholesterol levels. Of all nutrients assessed, only reduction of alcohol intake correlated with improvement of total serum triacylglycerol. CONCLUSIONS: Short-term dietary counselling in patients with endogenous hypertriglyceridemia can effectively improve serum lipid and lipoprotein levels. With regard to the advised nutrient changes, weight loss and limitation of alcohol intake prove to be the best predictors of triacylglycerol reduction.

Adult↗
PubMed1998

Hypertriglyceridemia and insulin resistance.

Although the association between insulin resistance and hypertriglyceridemia has long been recognized, the question of the causal relationship of these two entities is still a matter of debate. To gain more insight into the relationship between hypertriglyceridemia and insulin resistance, we studied insulin sensitivity in two severely hypertriglyceridemic subjects in whom insulin resistance as a cause for hypertriglyceridemia could be positively ruled out. Rather, lipoprotein lipase deficiency due to a mutation in the lipoprotein lipase gene was identified as the cause. In the two study subjects, whole body glucose utilization was measured during a continuous infusion of somatostatin, glucose and insulin. Mean values of plasma glucose and insulin concentrations at 150, 160, 170 and 180 minutes were used to calculate steady state plasma glucose (SSPG) and steady state plasma insulin (SSPI) concentrations. SSPG of the two hypertriglyceridemic patients was in the range of those reported in the literature for healthy subjects without insulin resistance did not differ from those of two control subjects with normal plasma lipid levels. Therefore, the dyslipidemic state of the two patients, characterized by extreme elevation of triglyceride rich plasma lipoproteins and a severe reduction of HDL cholesterol, was clearly not associated with insulin resistance. From these findings we conclude that hypertriglyceridemia per se is not an obligatory cause for insulin resistance.

Adult↗
PubMed1998

Role of secondary hyperparathyroidism in the genesis of hypertriglyceridemia and VLDL receptor deficiency in chronic renal failure.

Recent studies have revealed marked down-regulation of hepatic lipase (HL), lipoprotein lipase (LPL) and very low density lipoprotein-receptor (VLDL-R) expressions in animals with chronic renal failure (CRF). Acquired deficiency of these proteins, which together play an important role in catabolism of triglyceride-rich lipoproteins, is involved in the pathogenesis of CRF hypertriglyceridemia. Down-regulation of HL and LPL expressions in CRF can be completely reversed by parathyroidectomy (PTx), suggesting the role of excess parathormone (PTH). However, the role of hyperparathyroidism in the pathogenesis of CRF-induced VLDL-R deficiency has not been investigated before, and was studied here. To this end, VLDL-R mRNA (Northern analysis) and VLDL-R protein (Western analysis) of the fat pad and soleus muscle were compared in CRF (5/6 nephrectomized) rats, CRF animals with PTx (CRF-PTx) and sham-operated control animals. The CRF animals exhibited marked hypertriglyceridemia coupled with significant reductions in skeletal muscle and adipose tissue VLDL-R mRNA abundance and protein mass. Parathyroidectomy resulted in a significant, but partial, amelioration of CRF hypertriglyceridemia. However, in contrast to its effect on HL and LPL expressions, PTx did not improve VLDL-R expression, suggesting a PTH-independent mechanism for the latter abnormality. The differential effect of PTx on HL and LPL on the one hand and VLDL-R on the other can, in part, account for partial as opposed to complete correction of the associated hypertriglyceridemia with PTx in the CRF animals.

Adipose Tissue↗