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PubMed2001

Lack of triglyceride-lowering properties of fish oil in apolipoprotein e-deficient mice.

Fish oil is a potent triglyceride (TG)-lowering agent in humans. The goal of the present study was to assess the contribution of decreased triglyceride synthesis and of apoE in mediation of the triglyceride-lowering effect of fish oil. To this end, apoE-deficient mice and wild-type control mice were supplemented with either coconut oil, sunflower oil, or fish oil (20% wt/wt) for 2 weeks. Compared with coconut oil and sunflower oil, fish oil reduced the concentrations of cholesterol and triglycerides in the wild-type mice, whereas it had no effect on cholesterol concentration and it had a triglyceride-raising effect in apoE-deficient mice. The latter was due to increased triglyceride concentrations in the d<1.019 g/mL plasma density fraction. In apoE-deficient mice, but not in wild-type mice, the postprandial triglyceride area under the curve was higher after an intragastric load of fish oil than after a sunflower oil load. These data indicate an impairment of triglyceride metabolism in the fish oil-fed apoE-deficient mice. Compared with coconut oil and sunflower oil, fish oil lowered triglyceride production rates measured with the Triton method in both wild-type (P<0.0001) and apoE-deficient mice (P<0.0001). Similarly, in vitro lipoprotein lipase-mediated lipolysis of VLDL was lowered in the fish oil-fed wild-type and apoE-deficient mice, suggesting an alteration in VLDL lipolysis independent of the mice genotype. In conclusion, fish oil does not decrease triglyceride concentrations in apoE-deficient mice despite reducing triglyceride production rates, suggesting that decreased triglyceride synthesis is not sufficient to lower triglyceride concentrations in mice. ApoE appears to be necessary for fish oil to lower plasma triglyceride concentrations, indicating a critical role of apoE in this process.

Analysis of Variance↗

PubMed1972

Plasma triglyceride metabolism in thyroid disease.

Plasma endogenous triglyceride transport kinetics were determined in 16 hyperthyroid and in 12 hypothyroid patients and the results compared with those of euthyroid control subjects. In addition, the removal of exogenous particulate fat (Intralipid; Vitrum, Sweden) from the circulation and the postheparin plasma lipolytic activity (PHLA) were studied in these patients for further characterization of the alterations of plasma triglyceride metabolism in thyroid disease. In thyrotoxicosis the average plasma triglyceride level was slightly but significantly increased above that of control subjects. This change was associated with augmented production of triglycerides whereas the mean fractional removal rate was not different from normal. There was a significant linear correlation between the concentration and turnover rate of plasma triglycerides in both hyperthyroid and euthyroid subjects but the concentration/turnover rate ratio was less in the former group suggesting that the efficiency of removal of triglycerides from the circulation was improved in thyroid hyperfunction. The elimination of intravenously administered particulate fat occurred more rapidly in untreated hyperthyroid patients than in euthyroid control subjects. The mean PHLA was also above normal in thyrotoxicosis. Upon adequate treatment of the hyperthyroid state the fasting plasma triglyceride concentration was further increased. Hypothyroid patients showed another pattern of alteration of triglyceride kinetics. The synthesis of plasma triglycerides was normal but the fractional removal of both endogenous and exogenous triglycerides was markedly reduced and this change seems to account for the hypertriglyceridemia associated with thyroid hypofunction. The plasma PHLA was also clearly decreased in the hypothyroid state. Plasma FFA and glycerol levels were increased in hyperthyroidism and plasma FFA was slightly decreased in hypothyroid patients, but these variables were not significantly correlated with any parameter of triglyceride metabolism. Endogenous triglyceride turnover rate was significantly correlated with serum protein-bound iodine (PBI) and T3 uptake in thyrotoxicosis but not in hypothyroidism. Removal of exogenous fat was not related to postheparin plasma lipolytic activity but the fractional endogenous triglyceride transport showed a highly significant relationship to this lipase activity in a mixed group of hyper- and hypothyroid patients. The results suggest that thyroid hormones control both production and removal of plasma triglycerides. Different mechanisms for these interactions are considered.

Adolescent↗

PubMedDate not supplied

The effect of increasing levels of fish oil-containing structured triglycerides on protein metabolism in parenterally fed rats stressed by burn plus endotoxin.

This report investigates the effect of various levels of medium-chain/fish oil structured triglycerides on protein and energy metabolism in hypermetabolic rats. Male Sprague-Dawley rats (192 to 226 g) were continuously infused with isovolemic diets that provided 200 kcal/kg per day and 2 g of amino acid nitrogen per kilogram per day. The percentage of nonnitrogen calories as structured triglyceride was varied: no fat, 5%, 15%, or 30%. A 30% long-chain triglyceride diet was also provided as a control to compare the protein-sparing abilities of these two types of fat. Nitrogen excretion, plasma albumin, plasma triglycerides, and whole-body and liver and muscle protein kinetics were determined after 3 days of feeding. Whole-body protein breakdown, flux, and oxidation were similar in all groups. The 15% structured triglyceride diet maximized whole-body protein synthesis (p < .05). Liver fractional synthetic rate was significantly greater in animals receiving 5% of nonprotein calories as structured triglyceride (p < .05). Muscle fractional synthetic rate was unchanged. Plasma triglycerides were markedly elevated in the 30% structured triglyceride-fed rats. The 30% structured triglyceride diet maintained plasma albumin levels better than those diets containing no fat, 5% medium-chain triglyceride/fish oil structured triglyceride, or 30% long-chain triglycerides. Nitrogen excretion was lower in animals receiving 30% of nonnitrogen calories as a structured triglyceride than in those receiving 30% as long-chain triglycerides, but this difference did not reach statistical significance (p = .1). These data suggest that protein metabolism is optimized when structured triglyceride is provided at relatively low dietary fat intakes.

Animals↗

PubMed1992

The triglyceride connection in atherosclerosis.

OBJECTIVE: To examine the proposed mechanism of triglyceride-induced atherogenesis, to address the controversy surrounding serum triglycerides as a coronary heart disease (CHD) risk factor, and to recommend an appropriate therapeutic approach to hypertriglyceridemia. DATA SOURCES: Studies, review articles, and editorials published since 1976. A MEDLINE search of English-language literature was conducted using the terms triglyceride and hypertriglyceridemia. STUDY SELECTION: Studies, review articles, and editorials were selected for detailed review if they addressed the pathogenesis of triglyceride-induced atherosclerosis, the controversy associated with elevated serum triglyceride as a CHD risk factor, and hypertriglyceridemia treatment options. DATA EXTRACTION: Data were reviewed that described the atherogenicity of chylomicron and very low-density lipoprotein (VLDL) remnants, the inverse relationship that exists between high-density lipoprotein (HDL) and serum triglyceride, the hypertriglyceridemia treatment controversy, and the treatment options of diet, exercise, weight control, alcohol restriction, and medication. DATA SYNTHESIS: Hypertriglyceridemia is a well-known risk factor for pancreatitis. However, its role in atherogenesis is less well defined. Several proposed connections appear to exist between hypertriglyceridemia and atherosclerosis, including the inverse correlation between triglycerides and HDL, the presumed atherogenicity of triglyceride-rich lipoprotein remnant particles, the potential resultant increase in the serum concentration and atherogenicity of low-density lipoprotein (LDL), and the proposed interaction between serum triglyceride and the fibrinolytic/coagulation system. Clinical trials addressing this issue offer mixed results that are subject to interpretation. Diet, exercise, weight control, alcohol restriction, and certain lipid-lowering medications are effective at reducing serum triglyceride. CONCLUSIONS: Hypertriglyceridemia is a theoretical risk factor for CHD because of the increased production of atherogenic chylomicron and VLDL remnants, the inverse relationship present between serum triglyceride and HDL, the possible resultant increase in LDL attributable to remnant-reduced hepatic LDL-receptors as well as the formation of more dense and, therefore, more atherogenic LDL, and to the interaction between serum triglyceride and the fibrinolytic/coagulation system. However, most clinical trials that have found hypertriglyceridemia to be a risk factor for CHD do not include other CHD risk factors in their analyses. Therapeutic intervention to lower serum triglyceride with diet, exercise, and/or drugs is definitely recommended in the treatment and/or prevention of pancreatitis; however, the role of triglyceride-lowering to reduce CHD risk remains controversial.

Alcohol Drinking↗

PubMed2005

PPARalpha activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes.

Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARalpha activation, adenovirus-mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRP-overexpressing cells was unchanged. In summary, PPARalpha activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.

Acyl-CoA Dehydrogenase, Long-Chain↗

PubMed1997

Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small, dense low density lipoprotein.

A detailed longitudinal examination of plasma lipoprotein subfraction concentrations and compositions in pregnancy was performed with the objective of discovering the pattern of change in lipoprotein subfractions. Plasma triglyceride, cholesterol, very low density lipoprotein (VLDL1), very low density lipoprotein (VLDL2), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and its subfractions (LDL-I, LDL-II, LDL-III), and high density lipoprotein-cholesterol (HDL cholesterol) were quantified in 10 normal pregnant women from 10 weeks of gestation and at 5 weekly intervals thereafter, until 35 weeks of gestation, together with circulating hepatic lipase (at 10 and 35 weeks) and serum estradiol concentration. Median concentrations of VLDL1 (19-109 mg/dL), VLDL2 (17-103 mg/dL) and IDL (26-124 mg/dL) increased in parallel (maximum increase around 5-fold) as plasma triglyceride increased with advancing gestation. This contrasts with observations in the normal non-pregnant female, where higher concentrations of plasma triglyceride are associated with preferentially higher VLDL1 concentrations. The rise in IDL was also remarkable as this does not normally accompany changes in plasma triglyceride. LDL mass increased by 70% (200-353 mg/dL) between 10 and 35 weeks, and in 6 of the 10 women studied, the LDL subfraction pattern was modified towards a smaller denser pattern in a manner suggestive of a "threshold" transition, with the proportion of LDL-III increasing at the expense of LDL-II, whereas in the other 4 women, LDL subfraction profile remained unchanged throughout pregnancy. Interestingly, this "threshold" transition, if it occurred, did so at varying gestational ages and triglyceride concentrations for different women. The likelihood of LDL subfraction change and the final concentration of small, dense. LDL-III were related to the 10-week triglyceride concentration (R2 = 36.7%, P = 0.063) and to the rate of change in triglyceride for a given increment in estrogen (R2 = 48.6%, P = 0.025). In addition, VLDL1 mass exceeded 100 mg/dL during pregnancy only in those individuals in whom LDL profile perturbation was evident (chi 2, P < 0.001). LDL profile change was evident at the lowest triglyceride concentrations in the 2 individuals with the highest increments in triglyceride corrected for estrogen. On the basis of these longitudinal observations, we conclude the following: 1) as plasma triglyceride increases in pregnancy, there are parallel rises in median concentrations of VLDL1, VLDL2 and IDL, around 5-fold; 2) as a result of this progressive increase in plasma triglyceride, in particular in VLDL1, the LDL profile is altered in some individuals towards smaller, dense particles; 3) in general, the higher the initial (booking) fasting plasma triglyceride concentration or the larger the rate of change in triglyceride for a given increment in estradiol, the greater the probability of change in LDL profile towards smaller denser species; 4) significantly, LDL subclass perturbation towards smaller denser species occurs not in a gradual and progressive manner but exhibits "threshold" behavior; and finally, 5) this threshold is achieved at differing gestational ages and triglyceride concentrations for different women.

Adult↗

PubMed1993

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

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

Animals↗

PubMed1967

Endogenous triglyceride turnover in liver and plasma of the dog.

Radioactive glycerol and S(f) > 20 lipoproteins labeled with it were used to study turnover of plasma S(f) > 20 and hepatic triglyceride in anesthetized dogs. From specific activity-time curves of these lipids after an injection of labeled material, a tentative and incomplete model for the kinetics of endogenous hepatic and plasma triglyceride was defined and partially validated. Pool sizes and turnover rates of triglyceride in liver and S(f) > 20 lipoproteins of plasma were then calculated in seven dogs. Hepatic triglyceride was composed of two compartments: 60% metabolically inert and 40% metabolically active. Although communication between these hepatic compartments surely occurred during the time course of these studies, it was not sufficient to be detected by our present methods. The metabolically active compartment turned over as a single pool but with two destinations: a quite variable proportion (an average of 61%) was secreted into plasma as S(f) > 20 triglyceride, and an average of 39% was presumably hydrolyzed within the liver. The fractional turnover rate of plasma S(f) > 20 triglyceride was 2-3 times that of hepatic triglyceride. This finding, and the parallel decline of specific activities of plasma S(f) > 20 and liver triglyceride after injection of labeled glycerol, confirm the rate-determining role of hepatic triglyceride. In this respect the dog differs importantly from man. Though turnover rates of plasma S(f) > 20 triglyceride fell in the same range in men and dogs, the relationship of turnover rate to plasma concentration of this lipid differed greatly between them. The model for the dog does resemble that previously reported for man, however, in the lack of major recycling of intact plasma triglyceride between the liver and plasma. Lack of such recycling, however, does not exclude return of plasma triglyceride into a hepatic triglyceride sink. The amount of such unidirectional uptake, if any, could not be determined by these techniques.

Animals↗

PubMed1975

Turnover of plasma total and very low density lipoprotein triglyceride in man.

Basal plasma total triglyceride and very low density lipoprotein (VLDL) triglyceride turnover rates were determined in 110 subjects whose triglyceride concentrations ranged from low normal to markedly elevated values. The mean total triglyceride turnover rate was 13.7 mg - kg-1- hr-1, whereas the mean VLDL triglyceride turnover rate was 13.2 mg - kg-1 - hr-1. A highly significant correlation was present between the two turnover rates (r equal + 0.75). The endogenous serum triglyceride transported in the other lipoproteins (LDL and HDL) may account for more than half of the circulating triglyceride mass, but its significance in the total triglyceride transport is small. In a selected subgroup of 31 healthy subjects the plasma VLDL triglyceride concentration did not exceed 160 mg/100 ml. The range of this group's triglyceride turnover rate was completely comparable with most data reported in the literature for total serum or VLDL triglyceride transport in normal human subjects. When the turnover rate was plotted against the VLDL triglyceride concentration, three kinetic subgroups could be separated in accordance with the earlier experience on total serum triglyceride transport kinetics.

Body Weight↗

PubMed1990

Metabolic factors underlying high serum triglycerides in the normal hamster.

Comparative lipid metabolism of rats and hamsters was investigated to determine the metabolic basis for the relatively high concentrations of serum triglycerides in the hamster. It was found that serum free fatty acids (FFA) in the hamster are higher than in the rat in the fed condition. In addition, a higher percentage of the fatty acids esterified in the liver of the hamster is utilized for triglyceride synthesis. These factors combine to elevate hepatic triglyceride synthesis in the hamster. However, triglyceride does not accumulate in the liver in these animals in the fed state. In fact, liver triglycerides are lower in the fed hamster than in the fed rat, and the hamster stores much less triglyceride in liver lipid droplets than does the rat in this nutritional state. Most of the liver triglyceride in fed hamsters is present in dense particles corresponding to vesicular lipoprotein triglyceride in the secretory pool. In isolated organ perfusion experiments hamsters livers exhibited greater net triglyceride secretion than did rat livers. Serum triglycerides in the hamster remain elevated in the fasting state. In this condition the high proportion of free fatty acids utilized for liver triglyceride synthesis, relative to that incorporated into hepatic phospholipids, persists in the hamster and marked liver triglyceride accumulation occurs. Lipid droplets are extremely abundant in these livers. The present study implicates increased conversion of free fatty acids to triglyceride in the liver and increased hepatic production of very low density lipoproteins (VLDL) in the hamster in the genesis of the hyperglyceridemia characteristic of this species.

Animals↗

PubMed1989

Inhibition of acylcoenzyme A:cholesterol acyltransferase activity in CaCo-2 cells results in intracellular triglyceride accumulation.

The activity of acylcoenzyme A:cholesterol acyltransferase (ACAT) in CaCo-2 cells was inhibited by the ACAT inhibitor, 58-035. The inhibitory effect of this acylamide was specific for cholesterol esterification catalyzed by ACAT; the rates of triglyceride, phospholipid, and cholesterol synthesis were not inhibited by this agent. Cholesteryl esters were depleted in CaCo-2 cells 24 hr after inhibition of ACAT activity, whereas the unesterified cholesterol content increased by 56% after 96 hr. Moreover, inhibiting ACAT activity with 58-035 resulted in a time-dependent 2.5-fold increase in intracellular triglycerides. This accumulation of triglycerides in CaCo-2 cells was associated with a 37% increase in triglyceride synthesis by 96 hr in the presence of 58-035. Triglyceride-rich lipoprotein secretion (d less than 1.006 g/ml) was not affected by inhibiting ACAT activity for up to 6 hr. However, triglyceride-rich lipoprotein secretion was significantly decreased in CaCo-2 cells that were preincubated with 58-035 for 24 to 96 hr. Lipoproteins of density less than 1.006 g/ml that were isolated from CaCo-2 cells incubated with the ACAT inhibitor were deficient in cholesteryl esters and triglycerides compared to lipoproteins isolated from control cells. The data suggest that triglycerides accumulate in CaCo-2 cells in which ACAT activity has been inhibited by 58-035. This accumulation of triglycerides is associated with a modest increase in triglyceride synthesis and a decrease in triglyceride secretion. Altering intracellular cholesterol pools by regulating ACAT activity in the gut could result in the decrease of triglyceride transport and/or the secretion of triglyceride-rich lipoprotein particles of abnormal composition.

Acyl Coenzyme A↗

PubMed1998

Production of small high-density lipoprotein particles after stimulation of in vivo lipolysis in hypertriglyceridemic individuals: studies before and after triglyceride-lowering therapy.

In hypertriglyceridemic states, triglyceride enrichment of high-density lipoprotein (HDL) may play an important role in decreasing the HDL cholesterol and apolipoprotein (apo) A-1 plasma concentration. We have shown previously that HDL particles are transformed into small HDLs when lipolysis is stimulated in vivo or in vitro, and this process is more marked if the HDL is triglyceride-rich. The present study was conducted to determine whether the susceptibility of HDL to transformation can be altered by triglyceride-lowering therapy in humans. Seventeen moderately hypertriglyceridemic individuals (nine with type II diabetes mellitus and eight moderately hypertriglyceridemic nondiabetic subjects) were studied before and after 3 months of triglyceride-lowering therapy with gemfibrozil. Since no significant differences in postprandial and postheparin HDL metabolism were detected between type II diabetic and nondiabetic subjects, results are reported for the two groups combined (N = 17). Fasting HDL was triglyceride-rich with a preponderance of HDL3, and became more enriched with triglycerides postprandially. Heparin administration resulted in a rapid decrease in plasma and HDL triglycerides and an increase in plasma and HDL free fatty acids (FFAs). Postheparin, there was a reduction in HDL size and an increase in the proportion of small (HDL3c) HDL particles (HDL3c constituted 7.1% +/- 1.8% of total HDL preheparin and 26.6% +/- 3.8% postheparin, P < .001). Triglyceride-lowering treatment resulted in a decrease in fasting triglycerides (-54%, P < .001) and HDL triglyceride content (-36%, P = .002), an increase in fasting HDL cholesterol (19%, P = .004), and proportionately fewer (13.2% +/- 2.1%, P < .001) HDL3c particles formed postheparin. Postheparin HDL size correlated inversely with the fasting triglyceride level (r = -.55, P < .001) and HDL triglyceride concentration (r = -.34, P = .02). These results show that the postprandial increase in triglyceride levels in hypertriglyceridemic subjects is associated with increased production of small HDL particles when lipolysis is stimulated, and that lipid-lowering therapy can contribute to favorably reduce this postprandial production of small HDL particles. Further studies are needed to clarify how these abnormalities ultimately lead to a decrease of plasma HDL cholesterol and apo A-1 in hypertriglyceridemic states.

Female↗

PubMed1984

Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man.

Mechanisms for the hypolipidemic action of gemfibrozil were examined in seven patients with hypertriglyceridemia. In addition, seven hyperlipidemic patients were studied with and without clofibrate treatment to compare the mechanisms by which these two drugs lower plasma triglyceride levels. All patients were studied on a metabolic ward. The first month was a control period, followed by one month of either gemfibrozil or clofibrate therapy. During treatment with gemfibrozil, plasma total triglyceride levels decreased by an average of 51%, and triglyceride levels in very low-density lipoproteins (VLDLs) fell by 57%. Transport rates of VLDL triglyceride were determined by multicompartmental analysis following injection of tritiated glycerol as a precursor. Gemfibrozil decreased transport (production) of VLDL triglyceride by an average of 28% and increased the fractional catabolic rate (FCR) of VLDL triglyceride by 92%. Clofibrate reduced plasma total triglyceride values on an average of 32% and VLDL triglyceride values by 38%. In contrast to gemfibrozil, clofibrate did not change transport rates of VLDL triglyceride but increased the fractional catabolic rate of VLDL triglyceride by 35%. Gemfibrozil thus decreased production of VLDL triglyceride and enhanced its clearance, while clofibrate only increased clearance of VLDL triglyceride. On the average, plasma cholesterol levels did not fall during gemfibrozil treatment, but levels of cholesterol in high-density lipoproteins and in low-density lipoproteins increased by 31% and 11%, respectively. The drug produced a 30% increase in fecal excretion of neutral steroids and a 37% decrease in fecal excretion of bile acids. Outputs of total neutral steroids and net cholesterol balance thus remained unchanged.

Adult↗

PubMed1987

Coordination of very low-density lipoprotein triglyceride and apolipoprotein B metabolism in humans: effects of obesity and non-insulin-dependent diabetes mellitus.

To understand the relationship between very low-density lipoprotein (VLDL) triglyceride and VLDL apolipoprotein (apo) B, we studied their metabolisms simultaneously in 53 subjects with a range of obesity and glycemia. Obese subjects had increased production of both VLDL apo B and VLDL triglyceride and more VLDL of normal composition. Compared with nondiabetics, diabetic subjects had decreased clearance of both VLDL apo B and VLDL triglyceride, increased production of VLDL triglyceride but not of VLDL apo B, and more VLDL of abnormal composition. Production of both VLDL apo B and VLDL triglyceride were significantly correlated with plasma insulin concentrations, and rates of clearance of both were inversely correlated with plasma glucose. There was no direct correlation between total plasma free fatty acid concentration and production of either VLDL triglyceride or VLDL apo B, but VLDL triglyceride production was found to account for only a very small proportion of the nonoxidative component of free fatty acid turnover. We suggest that in obese subjects hyperinsulinemia induces overproduction of both VLDL apo B and VLDL triglyceride. In diabetes VLDL is increased in part because of decreased clearance; the altered composition is the result of the increase in VLDL-triglyceride production independent of apo B. The increase in VLDL triglyceride production may be mediated through plasma free fatty acids or glucose, although assessment of the relationship between these precursors and VLDL triglyceride is confounded by the fact that only a small portion of free fatty acids or glucose is converted to VLDL triglyceride.

Adult↗

PubMed1991

Effect of probucol on triglyceride turnover in streptozotocin-diabetic rats.

The long-term effect of probucol on triglyceride turnover was examined in streptozotocin (40 mg/kg) diabetic rats. Two diabetic groups were prepared: one group received a probucol-containing (1%) diet (probucol-treated diabetic) and the other standard diet (diabetic control). After 4 months of probucol diet, triglyceride turnover was estimated using Triton WR1339. In diabetic control rats, glucose, triglyceride and cholesterol concentrations in plasma and in the very low density lipoprotein (VLDL) fraction were markedly elevated and plasma insulin was suppressed compared to non-diabetic control rats. There was no significant difference in body weight, plasma glucose and insulin between the 2 diabetic groups. However, the probucol-treated diabetic group showed significantly suppressed levels of triglyceride and cholesterol in total plasma and in the VLDL fraction compared to each corresponding diabetic control value. On the other hand, there were no significant differences in triglyceride secretion rate between the 2 diabetic groups. Newly secreted VLDL particles after Triton injection from diabetic control rats were significantly cholesterol-enriched and triglyceride-depleted compared to those from non-diabetic control rats. However, the composition of those from probucol-treated diabetic rats was similar to that of non-diabetic control group. Prominent hypertriglyceridemia without increase in triglyceride secretion rate in diabetic control group indicates triglyceride removal defect in diabetic rats. Significant suppression of plasma triglyceride level without changes in the triglyceride secretion rate in the probucol-treated diabetic group suggests that probucol stimulated triglyceride removal in diabetic rats. Thus, probucol might normalize VLDL composition, thereby contributing to accelerated triglyceride removal from the circulation of streptozotocin diabetic rats without affecting glucose metabolism.

Animals↗

PubMed1992

Effect of mild diabetes and dietary fructose on very-low-density lipoprotein triglyceride turnover in rats.

Very-low-density lipoprotein (VLDL) triglyceride turnover was examined in mildly streptozotocin (25 mg/kg)-diabetic rats, using Triton WR1339. Diabetic rats fed standard rat chow showed mild hyperglycemia and suppressed levels of plasma insulin. Their triglyceride secretion was significantly suppressed despite an elevated level of plasma free fatty acids. However, the plasma triglyceride level of these diabetic rats was significantly elevated compared with nondiabetic controls. This suggested that the removal of triglyceride from the circulation, as well as its entry into the circulation, was impaired in mildly insulin-deficient rats. Glucose or fructose supplementation (10% in drinking water for 14 days) significantly increased the triglyceride secretion rate of diabetic rats. Especially, fructose supplementation increased plasma insulin to normal levels, but resulted in markedly elevated plasma triglyceride levels (three times higher than glucose-supplemented or chow-fed diabetic rats) despite similar triglyceride secretion rates between the two types of sugar-supplemented diabetic rat groups. This suggested an impairment of triglyceride removal by dietary fructose. The result obtained from chow-fed diabetic rats indicates that mild but significant insulin deficiency resulted in mild hypertriglyceridemia, linked to impaired triglyceride removal rather than to an overproduction of VLDL-triglyceride, despite elevated levels of plasma free fatty acids. Furthermore, fructose feeding induced prominent hypertriglyceridemia not only by stimulating triglyceride secretion, but also by suppressing triglyceride removal from the circulation of mildly diabetic rats.

Animals↗

PubMed1993

Effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on triglyceride kinetics in chronically streptozotocin-diabetic rats.

The effect of simvastatin (MK-733, Banyu, Tokyo, Japan), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on triglyceride kinetics, was studied in chronically streptozocin-diabetic rats. Diabetic rats, in whom diabetes was induced by a single intravenous injection of streptozotocin (40 mg/kg body weight) 2 months before the experiment, had significantly higher plasma glucose, triglyceride, and cholesterol levels compared with nondiabetic control rats, but triglyceride secretion rate was not increased. Both triglyceride secretion rate and plasma triglyceride level were significantly suppressed under nonfasting conditions in diabetic rats fed a (0.1%) simvastatin-containing diet for 10 days. After an overnight fast, their triglyceride secretion rate was not suppressed by this diet. However, their plasma triglyceride level was significantly (50%) suppressed, suggesting improved triglyceride removal from the circulation. In diabetic rats, the newly secreted triglyceride-rich lipoprotein particles were significantly cholesterol-enriched, but simvastatin had no effect on their lipid composition. These results suggest that the hypertriglyceridemia seen in chronically diabetic rats is mainly due to a triglyceride-removal defect, and that simvastatin reduces plasma triglyceride levels in these rats both by stimulating triglyceride removal and by reducing its entry into the circulation.

Animals↗

PubMed1989

The role of insulin in triglyceride turnover in rats.

Exogenously induced hyperinsulinemia can increase in vivo triglyceride production in rats receiving dietary fructose, either as monosaccharide or as sucrose, but not in those receiving only glucose. Thus, in the presence of fructose, but not glucose, insulin stimulates triglyceride production. Dietary fructose can also impair the removal of circulating triglyceride. Exogenous insulin overcomes this fructose-associated impairment of triglyceride removal. On the other hand, streptozotocin-diabetic rats showed a suppressed triglyceride secretion rate (TgSR) but their plasma triglyceride level was unchanged. Therefore, insulin deficiency may result in not only decreased production of triglyceride but also impaired triglyceride removal from the circulation. Fructose-fed diabetic rats showed higher plasma triglyceride levels than chow-fed diabetic rats without a concomitant increase in TgSR, suggesting impaired triglyceride removal from the circulation induced by fructose in diabetic rats. Glucose-fed diabetic rats did not differ in TgSR or plasma triglyceride level from chow-fed diabetic rats. These observations indicate that circulating insulin and dietary fructose, but not glucose, have a key role in very-low-density lipoprotein triglyceride turnover in rats.

Animals↗