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PubMed2003

Hypertriglyceridemia in patients with chronic renal failure: possible mechanisms.

Cardiovascular disease (CVD) is a major cause of mortality in patients with chronic renal failure (CRF) caused by numerous factors defined as traditional and uremia-related risk factors. One of these risk factors, dyslipidemia, is often observed in patients with CRF, resulting in abnormal concentrations and composition of plasma lipoproteins. The prominent features of uremic dyslipidemia are an increase in plasma triglycerides and cholesterol in nearly all lipoproteins, and a reduction in high-density lipoprotein (HDL) cholesterol. Because of its direct contact with the circulating blood, the endothelium is preferentially subjected to the modulatory effects of these altered lipoproteins. Little is known about the mechanisms for hypertriglyceridemia in CRF. This review highlights several studies over the past years that have contributed to knowledge of hypertriglyceridemia, especially in combination with renal diseases and their dialysis treatment. The underlying mechanisms behind hypertriglyceridemia have not been fully clarified and may indeed be multifactorial. Hypertriglyceridemia may contribute to the progression of atherosclerosis. Therefore, it is essential to study the putative mechanisms for uremic dyslipidemia, since optimal treatment is essential for the prevention or delay of cardiovascular complications in patients with CRF.

Humans↗
PubMed2000

Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles.

BACKGROUND: Endothelial dysfunction is considered one of the earliest events in the process of atherosclerosis, and an impaired vasodilatory response has been reported in patients with dyslipidemias. However, the independent association between hypertriglyceridemia and endothelial dysfunction is controversial, and the relation between endothelium-dependent vasodilation and circulating cell adhesion molecules as markers of endothelial dysfunction has not been fully determined. METHODS: Brachial artery flow mediated vasodilation (FMV) and the soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) were determined after overnight fasting in 16 men with hypertriglyceridemia (age 33 +/- 6 years) and in 16 age-matched healthy men with normal triglycerides and cholesterol. Subjects who smoked and those with known cardiovascular disease, diabetes, hypertension, recent or active infections, or any other disease that could affect leukocyte activation were excluded from the study. RESULTS: Compared with normal subjects, subjects with hypertriglyceridemia showed a higher level of sVCAM-1 and sICAM-1 (both P <.001), a reduced FMV (P <.01), and a smaller LDL particle size (P <.05). FMV had a significant inverse correlation with sVCAM-1 (r = -0.61, P <.001) and sICAM-1 (r = -0.38, P <.03). LDL particle size had a strong, direct association with FMV (r = 0.75, P <.001) and an inverse association with adhesion molecules. By multiple regression analysis, triglycerides (P <.001) and small LDL particle size (P <.002) predicted a reduced FMV. CONCLUSIONS: Serum level of cell adhesion molecules is increased and FMV is impaired in young healthy men with hypertriglyceridemia compared with age-matched men with normal lipid levels. Small, dense LDL particles may play a role in determining endothelial dysfunction in these subjects.

Adult↗
PubMed2004

Generation of a recombinant apolipoprotein E variant with improved biological functions: hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia.

To identify the residues in the carboxyl-terminal region 260-299 of human apolipoprotein E (apoE) that contribute to hypertriglyceridemia, two sets of conserved, hydrophobic amino acids between residues 261 and 283 were mutated to alanines, and recombinant adenoviruses expressing these apoE mutants were generated. Adenovirus-mediated gene transfer of apoE4-mut1 (apoE4 (L261A, W264A, F265A, L268A, V269A)) in apoE-deficient mice (apoE(-/-)) corrected plasma cholesterol levels and did not cause hypertriglyceridemia. In contrast, gene transfer of apoE4-mut2 (apoE4 (W276A, L279A, V280A, V283A)) did not correct hypercholesterolemia and induced mild hypertriglyceridemia. ApoE-induced hyperlipidemia was corrected by co-infection with a recombinant adenovirus expressing human lipoprotein lipase. Both apoE4 mutants caused only a small increase in hepatic very low density lipoprotein-triglyceride secretion. Density gradient ultracentrifugation analysis of plasma and electron microscopy showed that wild-type apoE4 and apoE4-mut2 displaced apoA-I from the high density lipoprotein (HDL) region and promoted the formation of discoidal HDL, whereas the apoE4-mut1 did not displace apoA-I from HDL and promoted the formation of spherical HDL. The findings indicate that residues Leu-261, Trp-264, Phe-265, Leu-268, and Val-269 of apoE are responsible for hypertriglyceridemia and also interfere with the formation of HDL. Substitutions of these residues by alanine provide a recombinant apoE form with improved biological functions.

Animals↗
PubMed2005

Acute pancreatitis during all-trans-retinoic acid treatment for acute promyelocytic leukemia in a patient without overt hypertriglyceridemia.

All-trans-retinoic acid (ATRA) has been successfully used in the treatment of acute promyelocytic leukemia (APL). One of its adverse effects is acute pancreatitis. In the literature, a proposed cause of acute pancreatitis is hypertriglyceridemia. Here, we present the case of a 45-year-old male with APL, treated with ATRA combined with induction chemotherapy (cytarabine and idarubicin), who developed acute pancreatitis without overt hypertriglyceridemia. This finding suggests that hypertriglyceridemia might not be the sole contributing factor in the pathogenesis of ATRA-induced acute pancreatitis and that attention should be paid to the possibility that ATRA treatment causes acute pancreatitis in the absence of overt hypertriglyceridemia.

Acute Disease↗
PubMed1990

Severe hypertriglyceridemia in diabetic ketosis.

In order to learn whether patients with diabetic ketosis who had very severe hypertriglyceridemia had underlying genetic hyperlipidemia, the authors measured plasma lipids in 211 episodes. They report the findings in the 15 patients who had initial plasma triglyceride concentrations above 11.3 mmol/L (1,000 mg/dL). These patients were detected during a prospective study of 155 episodes of ketoacidosis and 56 episodes of ketosis. Eleven of the 15 patients had definite or probable insulin-dependent diabetes mellitus (IDDM), but eight of the 15 were not acidemic despite their ketosis. Twelve of the 15 patients (80%) were men, a far higher percentage of men than the 53.6% in the base population of 211 episodes. Plasma triglyceride concentrations returned to normal levels either during the acute episode (seven cases) or well within a year (two more cases) in most of the patients. From that and other considerations, the authors infer that at least ten, and perhaps 12 of the 15 patients did not have an underlying genetic hyperlipidemia contributing to their original severe hypertriglyceridemia. That contrasts with the findings of others who reported that most patients with severe hypertriglyceridemia associated with noninsulin-dependent diabetes mellitus (NIDDM) (usually without ketosis) did have coexisting familial hypertriglyceridemia.

Adult↗
PubMed2003

Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in Taiwan.

INTRODUCTION: Familial lipoprotein lipase (LPL) deficiency is inherited as an autosomal recessive trait and is characterized by chylomicronemia, eruptive xanthoma, hepatosplenomegaly, and recurrent pancreatitis. AIMS AND METHODOLOGY: Two unrelated Chinese of Han descent with hypertriglyceridemia were enrolled in this study, and another six Han Chinese with no family history of hypertriglyceridemia and diabetes were recruited as normal controls. LPL activity was determined with use of an artificial substrate of 14C-trioleine and Arabic gum, and release of 14C free fatty acid was determined by the liquid-liquid partitioning system. LPL mass was measured by enzyme immunoassay. Genomic DNA was extracted from EDTA-preserved whole blood, and PCR was used to amplify the nine coding exons and the minimal promoter of the LPL gene. RESULTS: DNA sequence analysis revealed that mutations were identified in both patients; one patient had compound heterozygous mutations in codon 252 [CTG(Leu) --> GTG(Val)] and in codon 264 [TGC(Cys) --> TGa(Ter)] of exon 6, and the other patient had homozygous L252V mutation. These subjects had > or =90% reduction in LPL mass and > or =60% reduction in LPL activity. CONCLUSION: The mutated and truncated LPLs caused hypertriglyceridemia in these patients in Taiwan with hypertriglyceridemia and pancreatitis.

Adult↗
PubMed2004

Acute effects of premeal versus postmeal exercise on postprandial hypertriglyceridemia.

OBJECTIVE: The objective of this study was to examine the effects of the timing of exercise relative to the consumption of a fat-rich meal (81% fat) on postprandial hypertriglyceridemia. DESIGN: A single bout of exercise was either completed 30 minutes before the fat meal (EM trial) or initiated 90 minutes after the fat meal (ME trial). A third trial, fat meal only, served as a control (CON trial). The trials performed in a random order, and venous blood samples were drawn before and 1.5, 3.5, 5.5, and 7.5 hours after the meal for the determination of triglycerides, glycerol, insulin, glucose, and free fatty acids. PARTICIPANTS: Ten untrained healthy males 25.2 +/- 0.9 years old (mean +/- SE) with maximal oxygen uptake (VO2max) of 46.6 +/- 3.0 mL.kg(-1).min(-1). INTERVENTION: Walking exercise performed at 50% VO2max for 90 minutes. MAIN OUTCOME MEASURE: Postprandial hypertriglyceridemia, which was quantified by calculating the area under the triglycerides curve over the 7.5-hour postprandial period. RESULTS: The mean incremental area under the curve (total area adjusted to baseline) describing postprandial hypertriglyceridemia was lower both in the EM trial (3.16 +/- 0.99 mmol.L(-1).8 h) and in the ME trial (2.96 +/- 0.69 mmol.L(-1).8 h) compared with CON trial (6.18 +/- 1.10 mmol.L(-1).8 h; P<0.05). The corresponding areas under the curve describing the postprandial insulinemia were not different between trials (ME: 38.56 +/- 8.36 uIU.mL(-1).8 h; EM: 21.65 +/- 3.80 uIU.mL(-1).8 h; CON: 25.06 +/- 5.15 uIU.mL(-1).8 h; P>0.05). CONCLUSION: A single bout of moderate intensity exercise decreases postprandial hypertriglyceridemia irrespective of the timing of the exercise relative to a high-fat meal.

Adult↗
PubMed2004

Treatment of hypertriglyceridemia with omega-3 fatty acids: a systematic review.

PURPOSE: To (a) critically appraise available randomized controlled trials (RCTs) addressing the efficacy of long-chain omega-3 fatty acids as secondary agents for prevention of hypertriglyceridemia and (b) make recommendations for clinical practice. DATA SOURCES: Two independent reviewers examined all RCTs from 1994 to 2003 identified in several databases, extracted data from each study, and used the previously tested Boyack and Lookinland Methodological Quality Index (MQI) to determine study quality. CONCLUSIONS: Ten studies reported long-chain omega-3 fatty acids to be effective in the treatment of hypertriglyceridemia. The average decrease in triglycerides was 29%, total cholesterol 11.6%, very low density lipoprotein (VLDL) 30.2%, and low-density lipoprotein (LDL) 32.5%. One study found LDLs to increase by 25%. The average increase in high-density lipoprotein was 10%. The overall average MQI score was 36% (range = 26% to 54%). Many of the RCTs had serious shortcomings, including short duration, lack of a power analysis, no intention-to-treat analysis, no report of blind assessment of outcome, and lack of dietary control as a confounding variable. IMPLICATIONS FOR PRACTICE: Overall study methodology was weak. Although the evidence supporting use of long-chain omega-3 fatty acids in the secondary prevention of hypertriglyceridemia is reasonably strong, until there are larger RCTs of better methodological quality, it is not recommended that practitioners treat hypertriglyceridemia with omega-3 fatty acid supplementation in lieu of lipid-lowering medications.

Bias↗
PubMed1995

Myocardial lipoprotein lipase activity: regulation by diabetes and fructose-induced hypertriglyceridemia.

The decrease in myocardial lipoprotein lipase (LPL) activity observed previously in acute, severe models of insulin-deficient diabetes may be a compensatory response to hypertriglyceridemia and a sustained increase in fatty acid delivery to cardiomyocytes. The administration of fructose (10% solution in the drinking water for 4 days) to rats produced hypertriglyceridemia, but heparin-releasable LPL activity from perfused hearts and total and heparin-releasable LPL activities in isolated cardiomyocytes were not reduced. The acute (4 day) induction of a mild diabetic state (60 mg/kg streptozotocin) resulted in modest hypertriglyceridemia, and a selective decrease in heparin-releasable LPL activity in perfused hearts; LPL activity in cardiomyocytes from diabetic rat hearts was not reduced. Therefore, the diabetes-induced fall in myocardial LPL activity is not secondary to hypertriglyceridemia, since fructose treatment did not change LPL activity. Perfusion of rat hearts with 100 microM lysophosphatidylcholine (LPC) released a small amount of LPL activity into the perfusate, but only if albumin was omitted from the perfusion solution. Thus, the selective reduction in heparin-releasable LPL activity in perfused diabetic hearts is probably not the consequence of displacement by LPC, a lipolytic product of the LPL-catalyzed degradation of triacylglycerol-rich lipoproteins. Circulating LPL activity in the plasma of diabetic rats was not decreased relative to control plasma enzyme activity; therefore, the reduction in heparin-releasable LPL activity is not because circulating LPL was less available for uptake by the endothelium in diabetic hearts.

Adipocytes↗
PubMed1993

Determinants of fasting hypertriglyceridemia in ventromedial hypothalamic obesity in rats.

The present study investigated the mechanism of fasting hypertriglyceridemia in ventromedial hypothalamic (VMH) obesity by measurement of post-heparin plasma lipoprotein lipase (LPL) activity, triglyceride secretion rate (TGSR), and plasma insulin. One week after VMH lesions, when the lesioned rats were gaining weight rapidly (the dynamic phase), they showed normal plasma triglyceride levels with increased plasma LPL activity and TGSR. There was a positive correlation between hyperinsulinemia and elevated plasma LPL activity or TGSR in VMH-lesioned rats, while no correlation was observed in control rats. Ten weeks after VMH lesions, when the rats had become obese and reached a steady-state weight gain (the static phase), they showed hypertriglyceridemia with increased plasma LPL activity and TGSR. There was, again, a positive correlation between hyperinsulinemia and elevated plasma LPL activity or TGSR in VMH-lesioned rats. These results suggest a possible mechanism of fasting hypertriglyceridemia in these rats; in the dynamic phase adipose tissue adequately takes up circulating triglyceride because the tissue has sufficient take-up capacity and hence hypertriglyceridemia does not develop. In the static phase the tissue cannot adequately take up circulating triglyceride because of a limitation of its capacity, resulting in hypertriglycemia despite enhanced triglyceride secretion and increased LPL activity in both phases.

Animals↗
PubMed1991

Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia.

Plasma net cholesteryl ester (CE) transfer and optimum cholesteryl ester transfer protein (CETP) activity were determined in primary hypertriglyceridemic (n = 11) and normolipidemic (n = 15) individuals. The hypertriglyceridemic group demonstrated threefold greater net CE transfer leading to enhanced accumulation of CE in VLDL. This increased net transfer was not accompanied by a change in CETP activity. In normolipidemia, but not in hypertriglyceridemia, net CE transfer correlated with VLDL triglyceride (r = 0.92, P less than 0.001). In contrast, net CE transfer in hypertriglyceridemia, but not in normolipidemia, correlated with CETP activity (r = 0.73, P less than 0.01). Correction of hypertriglyceridemia with bezafibrate reduced net CE transfer towards normal and restored the correlation with VLDL triglyceride (r = 0.90, P less than 0.005) while suppressing the correlation with CETP activity. That net CE transfer depends on VLDL concentration was confirmed by an increase of net CE transfer in normolipidemic plasma supplemented with purified VLDL. Supplementation of purified CETP to normolipidemic plasma did not stimulate net CE transfer. In contrast, net CE transfer was enhanced by addition of CETP to both plasma supplemented with VLDL and hypertriglyceridemic plasma. Thus, in normal subjects, VLDL concentration determines the rate of net CE transfer. CETP becomes rate limiting as VLDL concentration increases, i.e., in hypertriglyceridemia.

Adult↗
PubMed1992

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum triglycerides of approximately 280 mg/dl, and a high expressor line with serum triglycerides of approximately 1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expressor mice and no differences were observed. Also, VLDLs obtained from control and high expressor mice were found to be equally good substrates for purified LPL. Thus excess apo CIII in HuCIIITg mice does not cause reduced VLDL FCR by suppressing the amount of extractable LPL in tissues or making HuCIIITg VLDL a bad substrate for LPL. Tissue uptake of VLDL was studied in hepatoma cell cultures, and VLDL from transgenic mice was found to be taken up much more slowly than control VLDL (P < 0.0001), indicating that HuCIIITg VLDL is not well recognized by lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased VLDL triglyceride, but not apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in triglyceride, but not apo B or total protein, secretion in high expressor mice compared with controls. In summary, hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common lipoprotein disorder.

Animals↗
PubMed2000

Use of arginine to reduce the severity of retinoid-induced hypertriglyceridemia.

Previous research with an animal model of retinoid-induced hypertriglyceridemia, rats fed a 13-cis retinoic acid-containing diet in which casein was the dietary protein, has demonstrated that replacement of dietary casein with soy protein isolate can reduce the severity of this condition. A depressant action of soy protein vs. that of casein on serum triglyceride concentration has also been demonstrated in rats fed purified diets without supplemental retinoid. Because this action of soy protein appears to be due to its having a higher arginine-to-lysine ratio than casein, a study was done to determine how feeding a casein-containing diet supplemented with sufficient arginine, to give a dietary arginine-to-lysine ratio equivalent to that of soy protein, would affect the development of retinoid-induced hypertriglyceridemia. Groups of five-week-old male Fischer 344 rats (n = 7/group) were fed a control diet containing casein or one of three 13-cis retinoic acid-containing diets in which dietary nitrogen was provided as casein, casein + arginine, or soy protein. Incorporation of dietary 13-cis retinoic acid resulted in hypertriglyceridemia, with serum triglyceride concentrations of 2.00 and 7.23 mmol/l, or 177 and 640 mg/dl, for groups fed the control and casein + 13-cis retinoic acid diets, respectively. For animals fed the 13-cis retinoic acid-containing diets, serum triglyceride levels for the casein + arginine and soy protein diet groups (4.75 and 2.92 mmol/l, or 421 and 258 mg/dl, respectively) were significantly lower than for the casein group (p < 0.05); however, the value was significantly lower for the group fed the soy protein diet than for the group fed the casein + arginine diet. Serum and dietary arginine-to-lysine ratios were highly correlated (r = 0.93, p < 0.0001). Thus, supplementing dietary casein with arginine reduced the severity of retinoid-induced hypertriglyceridemia, but not as effectively as replacing casein with soy protein.

Amino Acids↗
PubMed2002

Nateglinide suppresses postprandial hypertriglyceridemia in Zucker fatty rats and Goto-Kakizaki rats: comparison with voglibose and glibenclamide.

Postprandial hypertriglyceridemia, as well as postprandial hyperglycemia, are important factors contributing to the development of cardiovascular disease in patients with type 2 diabetes. Nateglinide is a recently approved antidiabetic that suppresses postprandial hyperglycemia by stimulating the early phase of insulin secretion. In the present study, we investigated the effects of nateglinide on postprandial hypertriglyceridemia in obese Zucker fatty (ZF) rats and non-obese diabetic Goto-Kakizaki (GK) rats. Administration of an oral fat load caused marked hypertriglyceridemia with a peak at 2 h in ZF and GK rats. Nateglinide (50 mg/kg) significantly suppressed the increase of plasma triglycerides after fat loading in both types of rat (delta AUC [0-4 h]: 15+/-69 mg.h/dl for nateglinide vs. 838+/-100 mg.h/dl for vehicle in ZF rats; p<0.01, 81+/-22 mg x h/dl for nateglinide vs. 164+/-17 mg.h/dl for vehicle in GK rats; p<0.01). In contrast, other antidiabetic agents (voglibose and glibenclamide) did not show a significant effect on the increase of triglycerides after fat loading. The triglyceride components suppressed by nateglinide were mainly at the origin and in the pre beta subfraction on agarose gel electrophoresis, suggesting that chylomicrons and very low density lipoproteins were decreased. Plasma insulin levels were significantly increased at 30 min in nateglinide-treated rats, but not in voglibose- or glibenclamide-treated rats. These results suggest that nateglinide not only suppresses postprandial hyperglycemia, but also suppresses postprandial hypertriglyceridemia, by promoting rapid and pulsatile insulin secretion in patients with type 2 diabetes.

Animals↗
PubMed2006

Capecitabine-induced severe hypertriglyceridemia: report of two cases.

OBJECTIVE: To report 2 cases of severe hypertriglyceridemia associated with the use of oral capecitabine. CASE SUMMARIES: The first patient was a 73-year-old woman with metastatic breast carcinoma who received capecitabine 2500 mg/m2/day in 2 divided doses for 2 weeks followed by a one week rest period. The baseline triglyceride level was 324 mg/dL; after 2 cycles of capecitabine, levels increased to 916 mg/dL. Although lipid-lowering treatment was initiated, triglyceride levels peaked at 1782 mg/dL by the end of the seventh cycle. Eight weeks after capecitabine treatment was stopped, triglyceride levels decreased to 118 mg/dL. The second patient was a 59-year-old man with metastatic colorectal carcinoma who was placed on capecitabine treatment at a dosage of 2500 mg/m2/day in 2 divided doses for 2 weeks followed by a one week rest period. The baseline triglyceride level was 244 mg/dL; levels peaked at 1455 mg/dL at the end of the fifth cycle. Capecitabine treatment was discontinued due to disease progression, and triglyceride levels decreased to 154 mg/dL after 11 weeks. DISCUSSION: The most frequently reported adverse effects of capecitabine are gastrointestinal and hematologic effects and palmar-plantar erythrodysesthesia. Drug-induced hyperlipidemia may appear more readily in individuals with hereditary lipoprotein lipase deficiency because decreased lipoprotein lipase activity might make these individuals more susceptible to a rise in triglyceride levels. The Naranjo probability scale indicated a probable relationship between capecitabine and severe hypertriglyceridemia. CONCLUSIONS: Capecitabine should be prescribed with care, especially in patients with preexisting hypertriglyceridemia. The question of whether capecitabine actually causes hypertriglyceridemia needs careful consideration, and the possible mechanism by which it may cause this adverse effect requires further investigation.

Aged↗
PubMed1999

Non-insulin-dependent diabetes mellitus and hypertriglyceridemia impair lipoprotein metabolism in chronic hemodialysis patients.

Patients with diabetes mellitus undergoing chronic hemodialysis treatment have the worst outcome on dialysis due to an increased rate of cardiovascular complications. Nearly all patients present with dyslipidemia, a prominent vascular risk factor, probably responsible for the high rate of vascular injury. Since both uremia and diabetes predispose to hypertriglyceridemia, the present study was conducted to investigate the influence of diabetes mellitus and/or hypertriglyceridemia on lipoprotein metabolism in hemodialysis patients. LDL was isolated and characterized from hyper- and normotriglyceridemic diabetic and nondiabetic hemodialysis patients (n = 40; 10 in each group); also, LDL-receptor-dependent uptake and intracellular cholesterol metabolism were studied in HepG2 cells. In addition, scavenger-receptor-mediated uptake was examined in mouse peritoneal macrophages. LDL isolated from nondiabetic normotriglyceridemic hemodialysis patients exhibited impaired cellular uptake via the LDL receptor. Additionally, intracellular sterol synthesis was less inhibited and cholesterol esterification was reduced compared with LDL from healthy control subjects. Reduction of catabolic capacities was more marked in hemodialysis patients who were either diabetic or hypertriglyceridemic and even more pronounced in patients presenting with a combination of both diabetes and hypertriglyceridemia. Hypertriglyceridemic and diabetic patients showed reduced lipase activity and increased LDL oxidation. Furthermore, they accumulated a fraction of small, dense LDL, and LDL was predominantly taken up via the scavenger-receptor pathway in peritoneal macrophages. This study elucidates the distinct influence of diabetes and/or hypertriglyceridemia in hemodialysis patients on cellular LDL metabolism via specific and nonspecific metabolic pathways. Furthermore, it underscores the cumulative impact of these pathologic entities on impairment of lipoprotein metabolism and increase of cardiovascular risk.

Aged↗
PubMed1996

Hypertriglyceridemia and low HDL cholesterol in Japanese patients with NIDDM.

Diabetes is frequently associated with the combination of hypertriglyceridemia and low HDL cholesterol level, a known risk factor for cardiovascular disease. We evaluated the frequency of elevated serum triglyceride and the reduced HDL cholesterol levels in Japanese male NIDDM patients. Hypertriglyceridemia (>1.69 mmol/l) and low HDL cholesterol level (<0.91 mmol/l) were frequently found in Japanese male (NIDDM patients (30.4 and 14.2%, respectively). The combined abnormality, i.e., hypertriglyceridemia with concomitant low HDL cholesterol level, was more common in patients with poor glycemic control. We observed that inpatient diet therapy markedly reduced serum triglyceride but serum HDL cholesterol did not change significantly. This is in marked contrast to primary hypertriglyceridemia, in which HDL cholesterol level generally increases in parallel with a reduction in serum triglyceride level. We discuss the defective removal of triglyceride-rich lipoproteins and ineffective HDL production caused by lipoprotein lipase (LPL) deficiency. We also discuss possible correction of this combined abnormality by certain maneuvers that increase LPL activity.

Adult↗
PubMedDate not supplied

Combination of gemfibrozil and orlistat for treatment of combined hyperlipidemia with predominant hypertriglyceridemia.

OBJECTIVE: To present a case of combined hyperlipidemia with predominant hypertriglyceridemia unresponsive to conventional diet and single-agent drug therapy but successfully treated with a combination of gemfibrozil and orlistat. METHODS: We describe a nonobese Asian Indian man with combined hyperlipidemia. Predominant hypertriglyceridemia was unresponsive to conventional therapy. Orlistat was added to the maximal dose of gemfibrozil, and baseline lipid profiles were compared with posttreatment values after repeated challenges with each drug individually and in combination. The relevant literature was also reviewed. RESULTS: At baseline, the patient's serum triglyceride level was 766 mg/dL and total cholesterol level was 241 mg/dL. On repeated measurements 4 months later, these values were 959 mg/dL and 309 mg/dL, respectively. With use of a reduced-fat diet and gemfibrozil (600 mg orally twice a day), serum triglyceride levels were 830 mg/dL and 909 mg/dL on two different occasions. Combination treatment with the same dosage of gemfibrozil and orlistat at 120 mg orally three times a day reduced triglyceride levels to 279 mg/dL and 244 mg/dL on two separate occasions. Rechallenges with drug monotherapy yielded triglyceride levels of up to 1,159 mg/dL with gemfibrozil alone and of up to 896 mg/dL with orlistat alone. A reduction of serum triglyceride levels to 269 mg/dL and 224 mg/dL occurred when combined treatment with both gemfibrozil and orlistat was reinstituted on two additional occasions. CONCLUSION: The combination of gemfibrozil and orlistat was extremely effective in reducing serum triglyceride levels in this patient with combined hyperlipidemia and predominant hypertriglyceridemia, whereas either one of these agents, when used alone, was ineffective. Determining the mechanisms of this synergy will necessitate further investigation. Additional studies of the use of the gemfibrozil-orlistat combination in patients who have combined hyperlipidemia with predominant hypertriglyceridemia are needed.

Adult↗