Triglyceride Levels In Rats Research Articles

Hypolipidemic activity and toxicity of 3-methoxy-N,N'-diaminophthalamide in rodents.

3-Methoxy-N,N'-diaminophthalamide was observed to be a potent hypolipidemic agent in rodents. Serum cholesterol and triglyceride levels in rats were significantly reduced as were lipid contents of the liver, small intestine, and aorta wall. VLDL and LDL cholesterol levels were significantly reduced. Unfortunately, HDL cholesterol levels were also markedly reduced. Furthermore, acute toxicity studies showed that the compound caused marked increases in serum CP kinase activity with doses of 40 and 100 mg/kg/day in mice. This is not a property of the 2,3-dihydrophthalazine-1,4-dione, the resultant product of the N,N'-diaminophthalamides. Apparently, closing the ring results in a safer compound with elevations in HDL cholesterol levels, a desirable characteristic in effective hypolipidemic agents.

Terephthalic Acid in Sprague‐Dawley Rats as a Hypolipidemic Agent

Terephthalic acid at 20 mg/kg/day in lowered serum cholesterol and triglyceride levels in rats. The cholesterol content was lowered in the lipoprotein fractions. The effects of the agents on de novo lipid synthesis showed that similar enzymes were affected in rat liver and small intestinal mucosa cells as when compared to in vitro tissue culture cells from rats and humans, e.g. reduction of acyl CoA cholesterol acyl transferase and elevation of neutral cholesterol ester hydrolase activities suggest that net cholesterol esters deposition in foam cells should be reduced and plaque growth should be slowed. The suppression of LDL receptor binding and degradation by the drug suggest that less apoB lipoproteins are taken up by peripheral tissues. The elevated HDL receptor binding and internalization in the liver suggest that the drug accelerates cholesterol return to the liver. Additional studies show that cholesterol and bile acid secretion in the bile is elevated. However, the bile acids secreted are not lithogenic. Acute toxicity studies show that the agent appears to be safe in rodents. Two observations of increased serum alkaline phosphatase levels and increased liver vacuolation suggest some alteration of hepatic cell morphology, which requires further investigation.

Effect of Exogenous or Endogenous Gastric Inhibitory Polypeptide (GIP) on Plasma Triglyceride Responses in Rats

We examined the effects of exogenous and endogenous GIP on plasma triglyceride levels in rats, pretreated with a fat-enriched diet, during intraduodenal infusion of a lipid test meal (Lipomul, 8 ml/h). Following the fat load the plasma triglyceride levels increased nearly linearly from a fasting value of 0.621 +/- 0.031 mmol/l to 3.32 +/- 0.403 mmol/l at 150 min. Simultaneously, the plasma GIP levels rose from 47.1 +/- 5.1 at fasting to a peak value of 268.4 +/- 32.2 pmol/l at 120 min. When porcine GIP was infused intravenously during the fat load, the plasma triglyceride increments were significantly smaller (control 1.64 +/- 0.264 mmol/l versus 0.949 +/- 0.114 mmol/l during GIP infusion at 60 min; p less than 0.002). GIP infusion in the absence of the fat load did not change fasting triglyceride levels. The effect of endogenous GIP was investigated by neutralization of GIP by injection of GIP antiserum (0.3 ml). Rats pretreated with the antiserum exhibited a significantly greater triglyceride increment late in the time course of the fat load. These data demonstrate that exogenous and endogenous GIP are able to lower the plasma triglyceride response to a fat load. Both, inhibition of fat absorption or stimulation of triglyceride uptake by peripheral tissues may be responsible for the GIP effects. The gut peptide GIP seems to represent an important hormonal regulator of postprandial triglyceride response.

In vivo triglyceride secretion and hepatic and plasma lipids in rats fed medium-chain triglycerides, tripelargonin, or corn oil

The relationship between in vivo triglyceride secretion and the concentrations of cholesterol and triglycerides in liver and plasma was studied in fasted, male Sprague Dawley rats (150–170 g) fed 16% fat diets containing 8–16% medium chain triglycerides (68% C 8:0 and 24% C 10:0), 14% tripelargonate (C 9:0), or corn oil. Plasma and liver cholesterol concentrations were 10–20% lower ( P < 0.05), and hepatic activity of 3-hydroxymethyl-3-glutaryl Coenzyme A reductase was 44–66% lower ( P < 0.05) with ingestion of 14% medium chain triglycerides or tripelargonin than corn oil. Liver triglyceride concentrations were 19–44% lower ( P < 0.01) with ingestion of 14% medium chain triglycerides or tripelargonin than corn oil. Using the Triton WR-1339 technique, the rate of triglyceride secretion (mg/min × 100 g body wt), plasma triglyceride pool size, and the fractional rate constant for triglyceride secretion were not significantly different among treatment groups. This suggests that a greater rate of triglyceride secretion is not the primary factor associated with lower hepatic triglyceride levels in rats fed medium chain triglycerides. In summary, 10–20% lower plasma and liver cholesterol concentrations were noted with ingestion of saturated, medium-chain-length fatty acid triglycerides containing 8, 9, or 10 carbons compared to corn oil.

Metabolic fate of chylomicrons obtained from rats maintained on diets varying in fatty acid composition.

The importance of the fatty acid component in the metabolism of chylomicrons was demonstrated by feeding diets varying in fatty acid composition which resulted in chylomicrons of different sizes. On a diet rich in polyunsaturated fatty acids (PUFA) from safflower oil, chylomicrons of diameter 1853 +/- 192 A were harvested from the mesenteric lymph, whereas on coconut oil and medium-chain triglyceride diets the chylomicron size was 1403 +/- 83 and 604 +/- 40 A, respectively. When the isolated chylomicrons were injected into recipient rats maintained on a regular diet, their half-life (t1/2) decreased from 5.4 +/- 0.4 to 1.8 +/- 0.3 min with the increase in particle size. No significant difference in the apolipoprotein profile of chylomicrons of various sizes was noted, indicating that alterations of chylomicron removal are not related to apolipoprotein composition. Rats maintained on PUFA diets showed a marked increase in their adipose tissue lipoprotein lipase activity. The fast removal of large chylomicrons and increased tissue lipoprotein lipase activity, together with suppression of hepatic lipogenesis on this diet, apparently explains the low plasma triglyceride level in rats maintained on diets rich in PUFAs.

Effects of Diets Rich in Fermentable Carbohydrates on Plasma Lipoprotein Levels and on Lipoprotein Catabolism in Rats

This study was conducted to examine the effects of a combination of several dietary fibers (5% guar gum, 5% apple pectin, 15% wheat bran, 22% soybean fiber) and crude potato starch (23%) on plasma lipids and lipoproteins and on liver lipid concentration in rats fed a diet containing either 15% lard or 5% oil with or without dietary cholesterol/cholic acid. Male Wistar rats ate the test diets for 3 wk. The incorporation of fiber and crude potato starch into the diet resulted in a significant enlargement of the cecum; it also increased the concentration of volatile fatty acids and the pool of acetate, propionate and butyrate. Feeding this fermentable carbohydrate decreased plasma cholesterol and triglyceride levels in rats given a low fat diet and prevented the expected rise in plasma cholesterol and triglycerides in rats fed cholesterol/cholic acid or lard. Further studies of high density lipoprotein (HDL) composition, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) activity and 125I-labeled human low density lipoprotein (LDL) turnover were done in the group fed the low fat diet without added cholesterol/cholic acid. The study of the HDL fraction in rats fed a diet rich in fermentable carbohydrates demonstrated a decrease in the HDL1 subpopulation and in the proportion of apolipoprotein E. Plasma clearance of intravenously injected 125I-labeled LDL was faster in rats fed this diet than in rats fed the fiber-free diet. In the liver, cholesterol and triglyceride levels were depressed whereas the activity of HMG-CoA reductase was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats

Insulin action was assessed by using the hyperinsulinemic (approximately 800 pmol/L) euglycemic clamp in rats fed equal amounts of glucose or fructose (35% of calories) for 4 wk. The glucose infusion rate required to maintain euglycemia was decreased in fructose-fed animals (14.6 +/- 1.4 vs 21.8 +/- 1.1 for glucose-fed rats, p less than 0.001) with this whole-body effect contributed to equally by an impairment in hepatic insulin action and a reduction in peripheral glucose disposal in a range of tissues. There was no difference in basal glucose turnover, energy expenditure, or postprandial blood glucose and insulin responses to the diets. In the fructose-fed rats there was an increase in fasting triglyceride levels by 2 wk. Euglycemic clamp glucose disposal correlated positively and clamp hepatic glucose output correlated negatively with fasting triglyceride levels. In summary, fructose but not glucose feeding led to impaired insulin action in both the liver and peripheral tissues, effects that may depend on antecedent circulating triglyceride levels.

Effect of activated carbon beads on serum lipid levels and fecal bile acid excretion in rats.

The effects of oral activated carbon beads on the total serum cholesterol and triglyceride levels and on the fecal bile acid excretion in rats fed a basal or high cholesterol diet containing 5% activated carbon beads for 6 weeks were investigated. The beads appeared to exert little effect on the growth rate of rats and no tendency towards constipation was also observed. Although treatment with activated carbon beads gave little influence on the total serum cholesterol and serum triglyceride levels in rats fed either a basal or high cholesterol diet, the beads did produce a significant rise in the total fecal bile acid excretion. The extra fecal bile acids resulted chiefly from an increase in lithocholic acid. Furthermore, the beads showed a tendency to inhibit absorption of dietary cholesterol from the gastrointestinal tract in rats fed a high cholesterol diet. These results suggested the possibility of activated carbon beads as a hypocholesterolemic agent through binding with bile acids in the intestine.

Hypolipidemic Activity of 3-N-(1′,8′-Naphthalimido)propionic Acid in Rodents

3-N-(1′,8′-Naphthalimido)propionic acid was synthesized and shown to effectively lower both serum cholesterol and triglyceride levels in rats and mice. In hyperlipidemic mice, serum lipid levels were lowered significantly, approaching normal levels of cholesterol and below normal levels of triglyceride. The serum lipid levels were reduced due to accelerated clearance of cholesterol via the biliary route as well as a lowering of available acetyl CoA in the cytoplasm for liver de novo cholesterol and triglyceride syntheses. The liver regulatory enzyme of fatty acid and triglyceride syntheses were depressed by drug treatment. Significant reduction of liver lipids as well as the lipid content of the lipoprotein fractions were observed. The agent possessed a safe therapeutic index when used as a hypolipidemic agent.

Hyperalphalipoproteinaemic activity of BRL 26314—I: Enhanced cholesterol turnover in rats

Administration of BRL 26314 [ N-(4-chlorobenzyl)- l-phenylalanine] raises circulating high-density lipoprotein (HDL) cholesterol and lowers total triglyceride levels in rats whether maintained on stock or semi-synthetic diets. HDL is also elevated by BRL 26314 in hypothyroid rats and in rats with pre-existing hyperlipidaemia where aortic total cholesterol concentration is decreased. BRL 26314 promotes the excretion of a dose of radiolabelled cholesterol as faecal sterols and bile acids, and decreases the extent of cholesterol-radiolabelling in tissue pools, particularly the aorta and adipose tissue. The increase in cholesterol and bile acid (cholic acid) turnover distinguishes BRL 26314 from a cholestatic agent such as 1-naphthyl isothiocyanate where a superficially similar change in HDL concentration disguises an impaired cholesterol transport. BRL 26314 is not a general protein inducer but part of the mechanism of action may involve enhancement of white adipose tissue lipoprotein lipase activity.

Antihyperlipidemic Activity of Phthalimide Analogues in Rodents

□ Phthalimide analogues have been shown to effectively lower serum cholesterol and triglyceride levels in rats and mice. The mode of action of these agents was not to suppress the appetite of animals, but rather to reduce the activities of key enzymes in the early synthesis of liver cholesterol and fatty acids in the triglyceride pathway. Phthalimide analogues were effective in accelerating biliary excretion of cholesterol and blocking its absorption from the gut. After 16 days dosing, it was evident that higher levels of lipids were being excreted than in control mice. The major serum lipoprotein fractions were reduced in cholesterol, triglyceride, and neutral lipid content, but not phospholipid content in rats after 14 days of administration.

Effects of Medroxyprogesterone Acetate and Caloric Restriction on the Distribution of Serum and Liver Lipids and Proteins in Female Rats

The effects of a large dose (2 mg/100 g body weight) of medroxyprogesterone acetate (MPA), restricted feeding (50% of normal intake) and their interaction were investigated on the serum and liver lipid and protein distribution in female rats. MPA increased serum cholesterol and triglyceride levels in rats on ad libitum food intake without having any effect in the animals on restricted diet. There was no statistical difference in the total serum protein or albumin levels among the groups. The serum levels of alpha and gamma globulin were significantly lower in the underfed rats. MPA increased the concentration of gamma globulin in well nourished rats but interacted with dietary restriction to further reduce the level of this protein in the undernourished animals. There was no difference in the levels of hepatic phospholipids or free cholesterol among groups. However, cholesterol ester and triglyceride levels in liver were significantly elevated in the MPA-treated group fed ad libitum. A similar increase was not found in underfed rats. This study indicates that MPA exerts significant effects on the distribution of serum and hepatic lipids and serum globulin levels and that the effects are dependent upon the nutritional status of the subject.progesterone lipids proteins undernutrition

Metabolic disorders associated with hyperlipemia: activity of an extremely potent hypolipemic agent (LR 19731).

LR 19731 [4-p-chlorophenyl-5-beta-(N'-phenyl)piperazinoethyl-1,3-dioxolin-2-one] lowers the plasma cholesterol and triglyceride levels of rats in several experimental conditions after single or repeated treatments, while it is scarcely active on liver lipids. The compound is especially effective in reducing plasma cholesterol in a dose-related manner both in normolipemic and hyperlipemic rats. The minimal effective dose (after five oral treatments in 4 days to normolipemic rats) is as low as 3 mg/kg, the ED50 is 11.3 mg/kg, while the maximal effective dose capable of completely suppressing plasma cholesterol is 100 mg/kg. Surgical removal of the thyroid gland does not influence its activity. At its ED50 the compound does not cause hepatomegaly, accumulation of desmosterol in plasma and liver. Under the same experimental conditions clofibrate presents a poor dose-response correlation on plasma lipids and generally appears at least 10 times less active than LR 19731 on cholesterol but more effective on liver weight. The experiments of general pharmacology indicate that LR 19731 does not effect central and peripheral nervous functions, does not influence the cardiovascular system or cause skeletal muscle relaxation, hypothermia, analgesia, and does not possess anti-inflammatory properties up to a dose of about 100 mg/kg.

The hypolipaemic action of a glycine rich diet in rats

Feeding of a glycerine rich diet with sufficient supply of essential amino acids (mixture of casein and gelatine) causes a significant reduction of the serum triglyceride level in rats. To study some aspects of this triglyceride lowering effect the in vivo incorporation of C14-1-acetate and C14-1-palmitate into the serum and liver lipids as well as the lipoprotein lipase and the hormone sensitive lipolytic activity of the epididymal adipose tissue in vitro were estimated. After feeding the gelatine containing diet the incorporation of labelled acetate and palmitate into the serum triglycerides was significantly decreased with no change of the incorporation into the liver triglycerides and without detectable accumulation of liver lipids. The decreased serum triglyceride level of the serum corresponded to a decreased lipoprotein lipase activity in the epididymal adipose tissue, whereas the basal and norepinephrine stimulated lipolysis of this tissue was not affected. From these results it is concluded that due to feeding of a glycine rich diet the triglyceride secretion of the liver is decreased leading to a lower serum triglyceride level.

Plasma Lipid and Lipoprotein Responses of Rats to Starch and Sucrose Diets with and without Brewer's Yeast

The effect of starch and sucrose diets, with and without brewer's yeast, on plasma total cholesterol and triglyceride concentration and on the lipoprotein distribution in plasma was studied in male rats. The rats were fed a cereal based stock diet, a starch or a sucrose diet, plus or minus brewer's yeast, for 4 weeks. The plasma cholesterol concentration increased to similar levels in rats fed the starch or the sucrose diets but remained unchanged in rats fed the stock diet. The plasma triglyceride level increased in rats fed stock diet, but was unchanged in those fed starch or sucrose diets. Brewer's yeast did not modify the cholesterol value in any of the three groups but reduced the triglyceride level in rats fed the stock and the starch diets. In rats fed the starch diet there was a reduction in the relative amount of prebeta lipoproteins, but no significant alterations in the beta, prealpha and alpha fractions, as compared with rats fed stock diet. Rats fed the sucrose diet had lower prebeta, beta and alpha lipoprotein percentages and a much higher prealpha percentage than rats fed the stock diet. Brewer's yeast had no consistent effects on the lipoprotein distribution. The results support the contention that there might be a dissociation between dietary effects on the plasma lipid level and on the lipoprotein distribution.

Influence of Sapogenins on Cholesterol Metabolism in Rats

SummaryRats were fed for four weeks on a basal fiber-free diet (B) or the same diet augmented with 1% cholesterol (BC). Diosgenin, tigogenin, hecogenin, β-sitosterol and their acetates (1%) were added to diet BC. Liver cholesterol and triglyceride levels of rats fed BC were significantly elevated compared to rats fed diet B (472 and 165%, respectively). The increases in liver cholesterol and triglyceride levels were significantly inhibited by all eight test compounds. When all rats were fed a single dose of [4-14C]cholesterol, appearance of isotope in serum and liver of animals fed the various steroids was up to 61% less than in rats fed diet BC. The acetates of hecogenin, tigogenin and β-sitosterol were more effective than the unesterified steroids in inhibiting cholesterol accumulation in liver.

The effect of high sugar intake on the esterification of dihydroxyacetone phosphate by rat liver microsomes

Rat liver microsomes were used as an enzyme source to study dietary-induced changes in the rate of dihydroxyacetone phosphate esterification. Rats were fed (1) 75% glucose or fructose diets for various time intervals, or (2) fed a fractose diet for six days and then a chow diet. Both the glucose and fructose diets produced a 2--3-fold increase in total and neutral glycerolipid formation from dihydroxyacetone phosphate measured in the presence of ATP, palmitate, CoA, and NADH. The increased rate of dihydroxyacetone phosphate esterification and a simultaneous rise in serum triglyceride level in rats fed fructose was rapidly reversed when chow was substituted for the fructose. The results indicate that an increased rate of dihyroxyacetone phosphate esterification may contribute to the acceleration of endogenous glycerolipid biosynthesis noted under these dietary conditions.

Nature of the Dietary Carbohydrate and Metabolism of Glycosaminoglycans and Glycoproteins in Rats

The polysaccharide from blackgram (Phaseolus mungo) has been previously reported to cause lower cholesterol, phospholipids and triglyceride levels in rats fed either low-or high-fat diets containing cholesterol. The effect of this polysaccharide fraction as compared to that of glucose and sucrose on the metabolism of glycosaminoglycans and glycoprotein has been studied. The pattern of change in the levels of different glycosaminoglycans varied in the different tissues. Sucrose fed animals gave lower levels of sulphated glycosaminoglycans in the aorta and liver. The polysaccharide and glucose fed animals gave comparable values in the aorta except in the case of chondroitin sulfate B which was higher and heparin lower in the polysaccharide group. L-glutamine:D-fructose-6-phosphate amino transferase and UDPG dehydrogenase were lowest in the sucrose fed animals and highest in the polysacchride group with the animals in the glucose group showing intermediate values, but UDPG pyrophosphorylase, while highest in the polysaccharide group, was similar in the glucose and sucrose groups. Some of the degrading enzymes studied-beta-glucuronidase, hyaluronidase and aryl sulphatase-were highest in the sucrose group and generally lowest in the polysaccharide group. Levels of 3'-phosphoadenosine-5'-phosphosulphate, the biological sulphating agent, the sulphate activating system which includes ATP sulphurylase and APS kinase and sulphotransferase activity were also lowest in the sucrose fed group and highest in the polysaccharide group. The glycoprotein concentration was highest in the liver and lowest in the kidney in the sucrose group.

Effect of p-chlorophenoxyisobutyrate on the antilipolytic action of insulin and insulin binding in isolated adipocytes

The present study was undertaken to investigate the potentiation by p-chlorophenoxyisobutyrate (CPIB) of the antilipolytic effect of insulin in isolated adipocytes from rats fed a (1) sucrose diet, (2) glycerol-lard diet, or (3) chow diet. CPIB supplementation in the diet consistently resulted in decreased serum triglyceride levels in rats from the three dietary groups. The catecholamine-stimulated glycerol release was significantly depressed to a greater extent by insulin when the fat cells were obtained from rats given CPIB compared to those without drug treatment. The enhanced insulin sensitivity was, however, not accompanied by any changes in insulin binding to adipocytes. These two observations were found in cell preparations from rats fed any one of the diets, although differences among dietary groups could be detected. In an in vitro experiment, epinephrine-stimulated glycerol release was progressively inhibited by increasing concentrations of CPIB in the incubation medium. However, the antilipolytic response to an optimal concentration of insulin (100 muU/ml) was augmented in the presence of CPIB. Thus, it seems that CPIB can potentiate the action of insulin in inhibiting mobilization of free fatty acid from the adipose tissue, and the coordinated effect of both antilipolytic agents is important in lowering serum triglyceride concentration. The mechanism by which CPIB facilitates the effect of insulin is discussed.

Effects of S-8527 (1,1-bis[4'-(1“-carboxy-1”-methylpropoxy)-phenyl]-cyclohexane), a new hypolipidemic compound, on triglyceride metabolism in rats

The effect of S-8527 (1,1-bis[4'-(1“-carboxy-1”-methylpropoxy)-phenyl]cyclohexane) on triglyceride metabolism was examined and compared with that of clofibrate in rats under various experimental conditions. In rats which were refed either a fat-free diet or a 5% fat diet after a 2-day fast, S-8527 at 30 mg/kg resulted in reductions of serum and liver triglyceride levels. In rats refed a fat-free diet, S-8527 showed a marked decrease in serum and liver triglyceride levels, but when rats were refed a 10% fat diet, the results were not significantly different from control. Clofibrate at 300 mg/kg lowered the liver triglyceride level in rats fed either a fat-free diet or a 5% fat diet but the effect was less than that of S-8527. In rats fed a normal commercial chow ad lib., an oral dose of S-8527 at 30 mg/kg for 8 days decreased the incorporation of [ 14C]acetate into liver triglyceride by about 50 per cent compared with that of controls, while clofibrate showed a slight increase in the labeled triglycerides in the liver. Addition of S-8527 to the normal rat liver slices at a concentration of 10 −5 M inhibited the triglyceride and phospholipid formation from [ 14C]acetate by about 40 and 50 per cent, respectively. S-8527 also inhibited rat liver acetyl-CoA carboxylase activity, but did not affect the activities of glucose 6-phosphate dehydrogenase, NADP-malate dehydrogenase, and citrate cleavage enzyme. These results suggest that the possible mechanism for the decrease in serum and liver triglyceride levels produced by S-8527 is an inhibition of triglyceride synthesis in the liver.