Antioxidant SMe1EC2 may attenuate the disbalance of sodium homeostasis in the organism induced by higher intake of cholesterol.

The study was focused to the influence of higher intake of cholesterol on properties of the renal Na,K-ATPase, a key system in maintaining the homeostasis of sodium in the organism. Feeding for 4 weeks with cholesterol-enriched food for rats afflicted with hereditary hypertriglyceridemia by itself enhanced the activity of Na,K-ATPase, probably as a consequence of higher number of active enzyme molecules as suggested by 32 % increase of V (max) value. This may be hypothesized as a reason for the increased retention of sodium. Three-week-lasting treatment of animals kept on high cholesterol diet with antioxidant SMe1EC2 in a dose of 10 mg kg(-1) day(-1) normalized the function of renal Na,K-ATPase to the level comparable in hypertriglyceridemic rats fed with the standard diet. Therefore, our results suggest that the antioxidant SMe1EC2 in the applied dose seems to be effective in the attenuation of cholesterol-induced retention of sodium. Treatment for 3 weeks with Fenofibrate in a dose of 100 mg kg(-1) day(-1) reversed the function of renal Na,K-ATPase only slightly.

Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies.

OBJECTIVE: Triglyceride-rich lipoproteins (TGRLs) are a cardiovascular risk factor and induce endothelial dysfunction. In the present study, we investigated the effects of post-prandial TGRLs from type IV hyperlipidemic subjects on endothelial activation addressing the effects of the lipoproteins on intracellular pathways and gene expression. METHODS: Thirty fasted hypertriglyceridemic patients were given an oral fat load (OFL) and blood samples were collected before the OFL (T0) and 2, 4, 6 and 8h thereafter. Endothelial function, determined as flow-mediated dilatation of the brachial artery, was assessed at the same time points. TGRLs were isolated at T0 and T4 (PP-TGRL) for in vitro studies. RESULTS: Compared with TGRLs, PP-TGRLs induced to a larger extent phosphorylation of p38 MAPK, CREB and IKB-alpha in human endothelial cells and increased the DNA binding activity of CREB, NFAT and NF-kappaB. Furthermore, PP-TRGLs upregulated the expression of several pro-inflammatory genes including vascular cell adhesion molecule-1 (VCAM-1), PECAM-1, ELAM-1, intercellular adhesion molecule-1 (ICAM-1), P-selectin, MCP-1, interleukin-6 (IL-6), TLR-4, CD40, ADAMTS1 and PAI-1. CONCLUSION: These effects may relate to the severe impairment of endothelial function seen during the post-prandial phase in hypertriglyceridemic patients.

Influence of genetic hyperlipemia in the Zucker rat upon the lipemic response to graded estradiol exposure.

The present investigation was designed to examine the influence of genetic Type IV hyperlipoproteinemia on the metabolism of lipids in response to estrogen exposure. The influence of 17-Beta-estradiol * was examined in a dose-response study over a range of hormone concentration from 10 to 100 pg/ml in genetic hyperlipidemic Zucker rats. In oophorectomized female rats, replacement levels of plasma estradiol of 40 pg/ml resulted in maximal hypertriglyceridemia of approximately 500 mg/dl representing a 5-fold exaggeration of that observed in control genetically norm-lipemic animals. This hypertriglyceridemia was associated with an increased production of triglyceride (TG) in excess of clearance, with a resulting production: clearance ratio of approximately 1.5. Exposure to maximum blood levels of estradiol, approximately 100 pg/ml, resulted in sub-normal levels of plasma TG (-145 mg/dl) in association with a reduced production: clearance ratio of approximately 0.36. In contrast to the marked hypocholesterolemic response to maximum estrogen exposure seen in normolipemic animals, the genetic Type IV hyperlipemic animal failed to demonstrate reduced plasma cholesterol concentration. This phenomenon was related to a rise in plasma LDL concentration in conjunction with parallel reduction in plasma HDL2 levels.Thus, an abnormal ratio of excessive LDL: HDl emerged in response to estrogen exposure in this model of human Type IV lipemia. This observation suggests that the genetic predisposition of the host may be critical to both the quantitative as well as the qualitative response to estrogen.

Influence on serum lipids, lipoproteins and blood pressure of mackerel and herring diet in patients with type IV and V hyperlipoproteinemia.

Eight patients with type IV and V hyperlipoproteinemia were put on a mackerel and herring diet of an isocaloric regimen for 2 weeks, in a cross-over design. At the end of the dietary periods a predominant increase of eicosapentaenoic acid (EPA - C20:5, n-3) in cholesterol esters and of docosahexaenoic acid (DHA - C22:6, n-3) in serum triglycerides, being more pronounced after mackerel as compared to herring diet, could be confirmed. After mackerel diet serum triglycerides and total cholesterol were significantly lower, returning to basal levels 3 months later. High density lipoprotein (HDL) cholesterol appeared slightly increased after mackerel diet and decreased to initial values thereafter. After herring diet, which contained half as much EPA as compared to mackerel diet, the differences were minor. The decline of free fatty acids (FFA) and insulin at the end of the mackerel period reached the level of significance 60 min and 120 min, respectively, after glucose load. A significantly lower systolic blood pressure in recumbent and upright position after the mackerel period could be found, whereas diastolic pressure and blood pressure after herring diet remained unchanged.

Fatty acid composition in fractions of structural and storage lipids in liver and skeletal muscle of hereditary hypertriglyceridemic rats.

The fatty acid (FA) compositions of liver and skeletal muscle structural lipids, overall phospholipids and phosphatidylcholine, and triglycerides (TG) were determined in the hereditary hypertriglyceridemic (HTG) rat, a nonobese animal model of the insulin resistance syndrome. Four groups of HTG rats and four groups of control animals were fed equal-energy diets for two weeks: basal (B), high-sucrose (HS), or fish oil-supplemented basal (BFO) or high-sucrose (HSFO) diets. In the liver of HTG rats, a decrease of n-6 long-chain polyunsaturated FA (PUFA), especially in 20:4n-6, in comparison with controls was found. Moreover, a concomitant accumulation of 18:2n-6 in structural lipids was observed. These differences were more pronounced in liver than in skeletal muscle. HS feeding raised the proportion of 18:1n-9 and decreased 18:2n-6 in lipid fractions. In both tissues and in both strains, the amounts of long-chain n-3 PUFA, as well as the level of total C20-22 PUFA, went up after fish oil feeding. However, the effects were somewhat less pronounced in the HTG rats. The increase in n-3 PUFA occurred mainly at the expense of reduced levels of 18:2n-6 in structural lipids and of 18:1n-9 in triglycerides. These changes were associated, in companion studies reported in this volume, with improved insulin action in HTG rats. In conclusion, the FA composition in lipid subclasses of HTG rats differs significantly from the controls mainly in liver structural lipids, suggesting the impairment of PUFA desaturation. Dietary change effected a similar modulation of FA profile across both strains, with fish oil increasing the levels of long-chain PUFA toward control values in the NTG rats. The HTG rat thus provides an interesting animal model for the study of impaired fatty acid metabolism.

The hypertriglyceridemic rat as a genetic model of hypertension and diabetes.

Hypertriglyceridemia was demonstrated in untreated hypertensive patients as well as in animals with genetic and experimental hypertension. The main purpose of the present study was to evaluate the possibility to use the hereditary hypertriglyceridemic (HTG) nonobese rats in hypertensive research. Direct measurement of blood pressure demonstrated significantly higher systolic, diastolic and mean arterial pressures in HTG rats in comparison with control Wistar rats. There was significant positive correlation between blood pressure and plasma triglyceride concentration (r = 0.585, n = 40, p less than 0.001). In addition, there were significantly increased plasma norepinephrine and epinephrine concentrations in HTG rats, suggesting that the stimulation of sympathetic nervous system could be one of the pathogenetic mechanisms involved in the increase of blood pressure of HTG rats.

A comparison of auditory brain stem evoked potentials in hyperlipidemics and normolipemic subjects.

Twenty-five hyperlipidemic, neurologically and audiologically asymptomatic patients were compared to 20 normolipemic control subjects regarding different interpeak latency differences (IPLD) of auditory brain stem evoked potentials (ABEP). ABEP were recorded in response to click stimuli presented at a rate of 10/sec and 55/sec. The net effect of increasing stimulus rate (ISR) on IPLD of ABEP was significantly greater in the hyperlipidemic patients for IPLD (V-I) and IPLD (III-I). ISR of ABEP indicates a trend of subclinical impairments of brain stem function in hyperlipidemic patients, probably due to ischemia accelerated by their condition.

[Platelet aggregation in whole blood and thromboxane B2 in type II and IV hyperlipidemia]. / Aggregazione piastrinica su sangue intero e trombossano B2 nelle iperlipemie di tipo II e IV.

Platelets play an essential role in the pathogenesis of atherosclerosis; by impedance method we valued in whole blood platelet aggregation induced by collagen in 40 healthy subjects and in 40 type II and type IV hyperlipemic subjects. Meanwhile by radioimmunoassay we dosed thromboxane B2, a stable product of thromboxane A2, released by platelets during activation, in 7 healthy subjects and 25 hyperlipemic subjects. The statistical investigation put in evidence that at higher plasmatic levels of cholesterol, triglycerides and LDL correspond a greater platelet sensitivity to the aggregating agent, while the opposite happens to higher levels of HDL. The dosage of thromboxane B2 put in evidence a moderate increase in hyperlipemic as to healthy subjects, probably pointing to a state of platelet activity.

[Platelet aggregation in whole blood and prostacyclin in hyperlipemia types II and IV]. / Aggregazione piastrinica su sangue intero e prostaciclina nelle iperlipemie di tipo II e IV.

Platelets play an essential role in the pathogenesis of atherosclerosis. Prostacyclin is a strong physiological inhibitor of platelets aggregation; prostacyclin indeed is involved in the regulation of platelet interactions with vessel walls and is considered to play a major role in the homeostatic balance. The impedance aggregometry allows the evaluation of platelet aggregation in whole blood. We valued platelet aggregation in whole blood induced by ADP (10 microM) in 40 healthy subjects and in 40 type II and type IV hyperlipemic subjects. Meanwhile by radioimmunoassay we dosed 6-keto PGF1 alpha, a stable product of prostacyclin, in 7 healthy subjects and in 33 hyperlipemic subjects. The statistical investigation put in evidence that at higher plasmatic levels of cholesterol, triglycerides and LDL correspond a greater platelet sensitivity to the aggregating agent, while the opposite happens to higher levels of HDL. The dosage of 6-keto PGF1 alpha put in evidence an increase of this substance in hyperlipemic as to healthy subjects, probably as an answer to augmented platelet aggregation.

Severe hypertriglyceridemia, large lipoproteins and protection against atherosclerosis.

Alloxan-diabetic cholesterol-fed rabbits exhibiting severe hypertriglyceridemia are protected against atherosclerosis. In such rabbits most of the plasma cholesterol is found in lipoproteins with a diameter of 75 nm or larger. In the present report it is hypothesized, that due to their large sizes, the lipoproteins of the severely hypertriglyceridemic diabetic rabbits are not able to penetrate the endothelial layer of the arteries. Therefore, the macrophages and smooth muscle cells of the intima will only come in contact with relatively small amounts of cholesterol-carrying lipoproteins. Consequently, cellular accumulation of cholesterol, which is a necessary step in the formation of an atherosclerotic lesion, will be retarded. There are certain parallels between hypertriglyceridemic cholesterol-fed alloxan-diabetic rabbits and humans with familial lipoprotein lipase deficiency, familial apolipoprotein C-II deficiency and insulin-dependent diabetes mellitus in the ketoacidotic state. Based on reports about patients with these metabolic disorders, we suggest that cholesterol in very large lipoproteins also in humans is less atherogenic than cholesterol in smaller lipoproteins.

Apolipoprotein A-V; a potent triglyceride reducer.

Since its discovery, apolipoprotein A-V has been considered to be a potent factor affecting plasma triglycerides (TG) in humans and mice. Several single nucleotide polymorphisms in the APOA5 gene are associated with increased TG levels in humans, and some nonsense mutations affecting protein structure predispose for familial hypertriglyceridemia and late onset chylomicronemia. It is not clear, how apoA-V decreases plasma TG. There are three major hypotheses: apolipoprotein A-V could work through (1) an intracellular mechanism affecting VLDL production in the liver, (2) stimulation of proteoglycan-bound lipoprotein lipase at the endothelium of capillaries in peripheral organs, or (3) enhancing the clearance of TG-rich lipoproteins via lipoprotein receptors in the liver. There is good evidence for a role of apoA-V in extracellular TG metabolism and increasing support for an additional function of ApoA-V as a receptor ligand. The intracellular role of apoA-V for lipoprotein assembly and secretion is still speculative. This review discusses these possible mechanisms.

Glucose intolerance and decreased early insulin response in mice with severe hypertriglyceridemia.

Hypertriglyceridemia (HTG) is one of the key features of dyslipidemia in type 2 diabetes, caused by the overproduction and/or decreased clearance of triglyceride (TG)-rich lipoproteins, and significantly promotes the development of cardiovascular diseases in diabetes. However, the effect of severe HTG on glucose metabolism has not previously been determined. Lipoprotein lipase (LPL) deficiency results in severe HTG in humans. By using LPL-deficient mice with severe HTG, we assessed the impact of severe HTG on insulin secretion and glucose tolerance in the present study. While young LPL-deficient mice (4 months of age) showed higher fasting blood glucose (7.42 +/- 0.84 versus 4.8 +/- 0.80 mmol/L, P < 0.01) and lower insulin concentrations (0.16 +/- 0.03 versus 0.48 +/- 0.14 ng/mL, P < 0.05), old mice (12 months of age) had higher insulin (1.70 +/- 0.35 versus 0.77 +/- 0.04 ng/mL, P < 0.05) but normal fasting blood glucose concentrations. Both young and old mice had elevated free fatty acid (FFA) concentrations and exhibited decreased early insulin response; however, only old mice showed impaired glucose tolerance, as compared with wild-type mice of a similar age. Morphological assessment showed enlarged islets in old LPL-deficient mice. These findings suggest that different tests for glucose homeostasis may be needed for patients with LPL deficiency and severe HTG, even though their glucose concentrations are normal at initial screening.

[Disturbance of exocrine secretion by the human pancreas in hyperlipoproteinemia]. / Perturbation de la sécrétion exocrine du pancréas humaine lors d'hyperlipoprotéinémie.

Basal and stimulated (secretin/CCK pancreozymin) duodenal aspirates were analyzed for flow rate and the protein and bicarbonate concentrations in 7 non-alcoholic controls and in 7 subjects with type IV hyperlipoproteinemia. Basal volume and bicarbonate concentration did not differ in the two groups. In the hyperlipoproteinemia patients, basal protein concentration and flow rates were significantly different from controls (p = 0.0143 and p = 0.0182 respectively). The bicarbonate flow rate is also increased in hyperlipoproteinemia. The data obtained after stimulation were similar for protein and HCO3 in both groups. These findings are identical to those observed by SARLES in alcoholic and hypercalcemic animals and in man. It is possible, but not yet proven, that hyperlipoproteinemia pancreatitis is due to protein precipitates in the pancreatic canaliculi.

Quantification of amounts of coronary arterial narrowing in patients with types II and IV hyperlipoproteinemia and in those with known normal lipoprotein patterns.

The amount of cross-sectional area narrowing by atherosclerotic plaques in each 5 mm long sement of the left main, left anterior descending, left circumflex, and right coronary arteries was analyzed at necropsy in 15 patients with type II hyperlipoproteinemia (HLP), in 13 with type IV HLP, and in 10 with known normal lipoprotein patterns. All 38 study patients had clinical evidence of coronary heart disease. Of the 2593 five mm segments examined histologically, narrowing of 76% to 100% in cross-sectional area by aterosclerotic plaques was as follows: type II = 39%, type IV = 67%, and normal lipoprotein pattern = 35% (controls = 4%). Utilizing a scoring system of 1 to 4 for the four categories of narrowing (0% to 25%, 26% to 50%, 51% to 75%, 76% to 100%), the mean score per 5 mm segment for the patients with type IV HLP was significantly higher (3.5) than that for the patients with type II HLP (3.0), normal lipoprotein patterns (3.0), and the controls (2.3). Thus, our patients with type II HLP and those with normal lipoprotein patterns had similar amounts of severe coronary narrowing and significantly less severe coronary narrowing than the patients with type IV HLP.