Dietary fat and hypercholesteremia in the Cebus monkey. II. Esterification and disappearance of cholesterol-4-C14

A series of studies of cholesterol metabolism in the Cebus monkey were carried out in an attempt to understand the mechanisms responsible for the great differences in serum cholesterol levels when different dietary fats were used. Three groups of monkeys, one fed diets including 45 per cent of calories as corn oil, a second corn oil plus cholesterol (0.1 gm./100 calories), and a third lard plus cholesterol for 5 months (mean serum cholesterol values were 237, 268, and 601 mg. per cent, respectively) were injected with emulsions of cholesterol-4-C¹⁴. The mean biological half-lives for the disappearance of serum radiocholesterol were 8.8, 8.4, and 6.6 days respectively. Esterification of radiocholesterol as measured by equilibration of specific activities of serum-free cholesterol and total cholesterol was delayed in the monkeys fed lard plus cholesterol. When cholesterol-4-C-¹⁴-stearate was given intravenously to a series of monkeys, an erratic non-exponential biological decay curve resulted. Specific activity for free serum cholesterol was greater than that for total cholesterol within 1 hour after the injection. After 7 months on experimental diets including corn oil with added cholesterol and lard with added cholesterol the levels of lipides in most tissues were not different for the two dietary groups, nor were they appreciably elevated above previous control figures for monkeys not fed cholesterol. Total lipide levels in the adrenals of monkeys fed corn oil were twice those of monkeys fed lard. Monkeys were fasted before and after intragastric administration of cholesterol-4-C¹⁴ in small formula meals including various fats and fatty acids. The disappearance of total cholesterol from the serum consisted of a rapid followed by a slow exponential function. The type of fat and fatty acid appeared to influence the rate of disappearance of radiocholesterol. There was a broad range of apparent activity of the different fats and fatty acids in promoting cholesterol absorption.     

Fatty Acid Incorporation into Human Adipose Tissue in Hypertrigiyceridaemia*

The fatty acid and glucose incorporation into glycerides and glycerol release from adipose tissue were determined in a middle-aged population of 109 men and 41 women. 43 men and 19 women were rrormolipidaemic. The same analysis was also carried out in 13 male and 9 female normolipidaemic students. Needle biopsy specimens of adipose tissue were incubated in vitro in an albumin medium containing ³H-fatty acids and ¹⁴C-glucose. After two hours of incubation values for fatty acid and glucose incorporation were calculated from the incorporation of ³H-activity into the fatty acids and ¹⁴C-activity into the glycerol moiety of extracted glycerides. The mean values for fatty acid incorporation were lower in all types of hypertriglyceridaemic subjects (II B, III, IV and V) than in the normolipidaemic control subjects. In the male hypertriglyceridaemic population 36 % had values for fatty acid incorporation below the 5th percentile of the normolipidaemic group and 14 % had values below the lowest normal value. The rate of fatty acid incorporation was negatively correlated with the serum triglyceride concentration. This correlation remained unchanged when partial correlation was performed when the influence of body weight was eliminated. Fatty acid and glucose incorporation correlated positively. Incorporation of glucose behaved in the same way as described above for incorporation of fatty acids. Glycerol and fatty acid release was the same in the normo- and hypertriglyceridaemic groups. It is likely that the removal of plasma triglycerides from blood requires hydrolysis of triglycerides to fatty acids and the subsequent removal of the fatty acids. The hypothesis has been formulated that when the former process is normal, a defect of fatty acid removal (a low rate of fatty acid incorporation into glycerides) may be responsible for an impaired removal of plasma triglyceride-fatty acids. A low rate of fatty acid incorporation may contribute to the development of hypertrigiyceridaemia, according to this hypothesis.     

Dietary saturated fatty acids increase cholesterol synthesis and fecal steroid excretion in healthy men and women

Abstract. In a strictly controlled 6-week trial with 47 healthy volunteers we have determined the effect of replacement of polyunsaturated by saturated fatty acids on the fecal steroid excretion and on the rate of whole body cholesterol synthesis, as measured both by the sterol balance method and by the concentration of the cholesterol precursor lathosterol in serum. Subjects were fed mixed natural diets, of which the total fat content was kept constant at 45% energy. Consumption of polyunsaturated fatty acids, mainly linoleic acid, was 21 % energy for the first 3-week period (P: S ratio 1.9), and 5% of energy (P: S ratio 0.2) for the next 3-week period, or vice versa. Cholesterol intake as determined by analysis of duplicate diets was 41 mg MJ^-1 (about 500 mg day^-1) during both periods. Feces were collected for 5 days at the end of both periods. The steroid composition of the feces was not affected by the change of diets. The fecal excretion of neutral steroids was significantly higher on the low P: S high-saturated-fat (2.25 ± 0.68 mmol day-¹) than on the high P:S high-linoleic-acid diet (2.00 ± 0.69 mmol day-¹; P < 0.01). The excretion of bile acids was similar (0.77 ± 0.40 and 0.79 ± 0.41 mmol day^-1, respectively). The cholesterol balance and the rate of cholesterol synthesis were higher during the low P:S (1.86 ± 0.83 mmol day^-1) than during the high P:S period (1.55 ± 0.85 mmol day^-1; P < 0.01). The ratio of lathosterol to cholesterol in serum was 0.86 ± 0.33 μmol mmol^-1 on the high-and 1.07 ± 0.39 μmol mmol^-1 on the low P: S diet (P < 0.01). Thus, both the balance and the cholesterol precursor method suggested that saturated fatty acids stimulate whole-body cholesterol synthesis.     

Resveratrol inhibits fatty acid and triacylglycerol synthesis in rat hepatocytes

Background The putative role of resveratrol, a polyphenol present in grapes and other plants, in modulating dislypidemia, thus preventing cardiovascular diseases, is generally based on proliferating cell lines and in vivo studies in different pathological conditions. The aim of the present study was to investigate whether resveratrol plays a role on lipid biosynthesis in rat hepatocytes. Materials and methods The effect of resveratrol on total rate of fatty acid, cholesterol and complex lipid synthesis, assayed by the incorporation of [1‐¹⁴C]acetate into these lipid fractions, was investigated in rat hepatocyte suspensions. Enzyme activities of acetyl‐CoA carboxylase (ACC) and fatty acid synthase (FAS) as well as 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase (HMG‐CoA‐R), pace‐setting steps of de novo fatty acid and cholesterol synthesis, respectively, were in situ measured in digitonin‐permeabilized hepatocytes. Results Resveratrol‐treated hepatocytes exhibited a short‐term (30 min) inhibition (IC₅₀ ~25 µm ) of total fatty acid synthesis from [1‐¹⁴C]acetate. Among neosynthesized fatty acids, palmitic acid formation was mainly reduced, thus suggesting that enzymatic step(s) of de novo fatty acid synthesis was affected by resveratrol. In digitonin‐permeabilized hepatocytes, only ACC activity was noticeably reduced, while no change in FAS activity was observed. A noticeable resveratrol‐induced reduction of label incorporation into triacylglycerols was also detected. Conversely, cholesterol synthesis and HMG‐CoA‐R activity were unaffected by resveratrol. Conclusion Results here reported show that in isolated hepatocytes from normal rats a resveratrol‐induced short‐term inhibition of fatty acid and triacylglycerol synthesis occurs. This finding may represent a potential mechanism contributing to the reported hypolipidemic effect of resveratrol.     

Sex Steroid Modulation of Fatty Acid Utilization and Fatty Acid Binding Protein Concentration in Rat Liver

The mechanism by which sex steroids influence very low density hepatic lipoprotein triglyceride production has not been fully elucidated. In previous studies we showed that [¹⁴C]oleate utilization and incorporation into triglycerides were greater in hepatocyte suspensions from adult female rats than from males. The sex differences were not related to activities of the enzymes of triglyceride biosynthesis, whereas fatty acid binding protein (FABP) concentration in liver cytosol was greater in females. These findings suggested that sex differences in lipoprotein could reflect a sex steroid influence on the availability of fatty acids for hepatocellular triglyceride biosynthesis. In the present studies, sex steroid effects on hepatocyte [¹⁴C]oleate utilization and FABP concentration were investigated directly.     

Substituting polyunsaturated for saturated fat as a single change in a Swedish diet: effects on serum lipoprotein metabolism and glucose tolerance in patients with hyperlipoproteinaemia

Abstract. A diet with a high content of polyunsaturated fatty acids (PUFA) with a ratio between polyunsaturated and saturated fatty acids (P/S) of 20 and a fat content of 44% was worked out. After an initial 2 weeks' period on a control diet (P/S ratio 0–2) the PUFA diet was fed under isoenergetic conditions at a metabolic ward for 2 weeks to thirty patients with hyperlipoproteinaemia type IIa (n= 7), type IIb (n= 5) and type IV (n=18). The two diets were based on ordinary foodstuff and differed only in regard of the quality of the fat, while the amount of fat as well as the content of other nutrients were kept constant. Compared with the control diet the serum cholesterol concentration decreased by 10%, 13% and 12% on the PUFA diet in patients with hyperlipoproteinaemia type IIa, IIb and IV respectively. In hyperlipoproteinaemia Ila the low density lipoprotein cholesterol decreased by 9% (n.s.) and the high density lipoprotein cholesterol by 16% (P < 005). In hyperlipoproteinaemia type lib the very low density lipoprotein cholesterol decreased by 18% (P < 005), the low density lipoprotein cholesterol by 13% (P < 005) and the high density lipoprotein cholesterol by 5% (n.s.). In type IV the very low density lipoprotein cholesterol decreased by 18% (P < 0–01), the low density lipoprotein cholesterol by 7% (P < 0–05)) while the high density lipoprotein cholesterol remained unchanged. The serum triglyceride concentration decreased by 10% (type IIa), 14% (type lib) and 13% (type IV) on the PUFA diet. The serum concentrations of apolipoprotein A-I and B were reduced by 6% (P < 0–05) and 11% (P < 005) respectively in patients with hyperlipoproteinaemia type IV while the serum apolipoprotein concentration did not change in the patients with hypercholesterolae-mia. Inverse relationships between very low density lipoprotein triglycerides and high density lipoprotein cholesterol were found before treatment (r= 0–49, P < 0–01) which was altered by the treatment (r= 0–28, P > 005). The very low density lipoprotein triglycerides were also found to be inversely related to low density lipoprotein cholesterol both on the control diet (r= -0–65, P < 0001) and the PUFA diet (r= -0–56, P < 001). The regression lines of the latter equations were parallel. The intravenous glucose tolerance was improved (P < 0 05) in patients with hyperlipoproteinaemia type IV on the PUFA diet. The fatty acid composition of the serum lipid esters was significantly changed during the treatment. The relative concentrations of oleic acid and saturated fatty acids decreased while the linoleic acid content increased. The effects of the PUFA diet were less pronounced than the effects of conventional lipid lowering diets where also the fat content has been reduced and where complex carbohydrates have been substituted for simple carbohydrates.     

Free fatty acid and carbohydrate metabolism of the working forearm muscle in type IV hyperlipoproteinaemia

Abstract. Substrate utilization of the working forearm was studied in nineteen patients with hypertriglyceridaemia (HLP) and compared to nineteen normolipidaemic (NLP) subjects, matched with regard to body weight, body height, intravenous glucose tolerance and age. Arterial-deep venous differences of oxygen, carbon dioxide, free fatty acids (FFA), glucose, lactate and pyruvate was measured. The fractional extraction and oxidation of fatty acids was assessed by intravenous infusion of albumin-bound [³H]palmitate and [¹⁴C]oleate. Measurements were made both in the postabsorptive state and after plasma FFA lowering by nicotinic acid. The HLP subjects had, before nicotinic acid, higher arterial concentrations, higher turnover rates of palmitate and oleate and higher plasma glycerol concentrations indicating a greater mobilization of FFA. However, the forearm extraction and oxidation of FFA as well as the calculated total body fatty acid oxidation was similar in HLP and NLP subjects. Nicotinic acid decreased arterial concentrations and turnover rates of FFA to the same extent in HLP and NLP groups, the effect being the same for palmitic and oleic acid. Fractional extraction both of palmitic and of oleic acid increased after nicotinic acid in the NLP but not in the HLP group. Plasma glycerol decrease after nicotinic acid was of the same magnitude in HLP and NLP groups. Thus, (1) an increased uptake of FFA in HLP subjects must occur in other tissues than skeletal muscle and with another fate of the fatty acids than oxidation. The explanation might be an increased incorporation of fatty acids into triglycerides which are subsequently secreted from the liver. (2) The impaired triglyceride removal in skeletal muscle which has been found in HLP subjects is more likely due to an impaired lipolytic activity than to an abnormality in uptake and utilization of hydrolysed fatty acids. No abnormalities in carbohydrate metabolism were found in these HLP subjects with normal glucose tolerance.     

Pathways of fatty acid metabolism in human platelets

The metabolic fate of ¹⁴C-labeled fatty acids which have been incubated with human platelets, has been traced. The following has been shown. (a) Intact platelets have a considerable capacity to oxidize fatty acids. (b) When tracer amounts of four of the most common fatty acids in normal plasma were incubated with platelets, each showed a distinctive pattern of uptake among neutral lipids and phospholipids. With regard to the latter, it was shown that these distribution patterns were, in most cases, similar to those of the fatty acids found in natural platelet phospholipids. (c) By increasing the time of incubation or the amount of added oleic acid, the distribution of oleic acid uptake between lecithin and other phosphoglycerides was altered so that a larger share was incorporated into the latter. (d) The effects of added lysolecithin or lysoethanolamine phosphoglycerides on oleic acid incorporation into platelet phosphoglycerides are quite variable. At low concentrations, added lysolecithin functions chiefly as a reaction partner for oleic acid. Added adenosine triphosphate and CoASH augment the incorporation of oleic acid into lecithin over a wide range of added lysolecithin (12.5-500 μmoles/liter). At higher concentrations of added lysolecithin, in the absence of ATP and CoASH, oleic acid incorporation into lecithin is considerably reduced. Also, added lysolecithin and lysoethanolamine phosphoglycerides, in the absence of ATP and CoASH, are able, at certain concentrations, to stimulate oleic acid incorporation into all except the serine phosphoglycerides. (e) Platelets appear to have a de novo pathway for renewal of lecithin.     

Biosynthetic origin of serum cholesterol in the squirrel monkey: evidence for a contribution by the intestinal wall

The possibility that the intestinal wall serves as a biosynthetic site for serum cholesterol has been examined in two types of studies in the squirrel monkey. First, animals were fed cholesterol in order to inhibit cholesterol synthesis in the liver, and the intestinal lymph ducts were cannulated. After the administration of acetate-2-¹⁴C it was possible to demonstrate that cholesterol synthesized by the intestinal wall enters intestinal lymph and thereby in the intact animal enters the circulating pool. Second, an attempt to quantitate the significance of this intestinal contribution has been made in animals fed cholesterol-3-³H and injected with cholesterol-4-¹⁴C for long periods. By an application of the technique of analysis utilizing the isotopic steady state we estimated as a minimal value that in the squirrel monkey 1.5-2.0 mg of cholesterol synthesized in the intestinal wall reaches the circulation each day.     

Secreted and intracellular phospholipases A2 inhibition by 1-decyl 2-octyl-glycerophosphocholine in rat peritoneal macrophages

Summary— Compounds able to inhibit phospholipases A₂ can be considered as potential anti-inflammatory drugs. In this respect, the inhibitory effect of the phospholipid analogue 1-decyl 2-octyl-rac-glycero-3-phosphocholine (decyloctyl-GPC) added to the culture medium of rat peritoneal macrophages stimulated with ionophore A23187 was determined, (a) The substrate of phospholipase A₂ 1-octadecanoyl 2-[¹⁴C]eicosatetraenoyl-sn-glycero-3-phosphocholine ([¹⁴C]20:4-GPC) was added to the culture medium. In macrophages + extracellular fluids, its hydrolysis at the 2-position, produced [¹⁴C]non-phosphorous lipids which reached 12% of the dose at 0.14 μM, 73% at 0.9 and > 90% at 1.6 μM; in experiments where macrophages and extracellular fluids were analyzed separately, decyloctyl-GPC initially added at 4 μM, significantly inhibited the release of [¹⁴C]fatty acids and the eicosanoid synthesis, demonstrating its ability to inhibit secreted and/or intracellular phospholipases A₂. (b) Extracellular fluids were separated from the macrophages and incubated with [¹⁴C]20:4-GPC: 48% of the dose was hydrolyzed by extracellular fluid-associated secreted phospholipase A₂ and decyloctyl-GPC at 3 μM, reduced this hydrolysis by 50%. (c) [³H]arachidonic acid ([³H]20:4) was added to the culture medium and was esterified in the macrophage membrane phospholipids. Activation of intracellular phospholipase A₂ induced the release of [³H] fatty acids and eicosanoid synthesis. These releases were inhibited by 50% with decyloctyl-GPC added at 4 μM. (d) [³H]20:4 and [¹⁴C]20:4-GPC were added to the culture medium of the macrophages. [³H] and [¹⁴C] fatty acids and eicosanoids were released in macrophages or extracellular fluids. They were significantly reduced by the phospholipid analogue added at 4 μM. It is concluded that secreted and intracellular phospholipases A₂ were both inhibited by decyloctyl-GPC which extensively reduced the 20:4 release from exogenous and membrane phospholipids and therefore eicosanoid synthesis.     

Fat metabolism following an intravenous bolus dose of a fat emulsion and carnitine

Summary. Intravenous fat tolerance tests were performed with (carboxyl-¹⁴C)-triolein labelled Intralipid® in four normal subjects with and without L-carnitine administration, 20 and 25 mg/kg body weight. The pharmacokinetics of L-carnitine was studied simultaneously with measurements of variables reflecting fat metabolism during 4 h. 3-OH-butyrate concentration in plasma was higher in all subjects when carnitine was given. No effect of carnitine was found in elimination of the exogenous triglycerides, the ¹⁴CO₂ activity in expired air, concentration and specific radioactivity of non-esterified fatty acids or glucose in plasma. The data suggest that carnitine may slightly increase fatty acid oxidation in normal subjects provided that increase of 3-OH-butyrate concentration in plasma is the most sensitive variable reflecting fatty acid oxidation of the variables applied in this study.     

Membrane fatty acids and erythrocyte Li-Na countertransport in nephrotic syndrome and their relationship

Summary Cholesterol/phospholipids molar ratio and fatty acid composition have been estimated in erythrocyte membrane of 12 patients suffering from nephrotic syndrome and compared to values obtained in 23 normal subjects matched for sex and age. The membrane lipid composition has been correlated with the activity of erythrocyte Li-Na countertransport of the same subjects. The results show a significant increase in cholesterol/phospholipids ratio and total saturated fatty acids when erythrocytes of nephrotic patients are compared to normal erythrocytes, whereas total unsaturated fatty acids were lower in nephrotics (p<0.002). Li-Na countertransport was higher in nephrotics (p<0.001) and it was positively correlated with the total amount of saturated fatty acids of the erythrocyte membrane (r=+0.451; p<0.01). On the contrary, Li-Na countertransport was negatively correlated with the total amount of unsaturated fatty acids (r=−0.468; p<0.01). This work was supported by a grant (84.857.04) fromConsiglio Nazionale delle Ricerche (CNR), Roma, Italy.     

Dietary supplementation with very long-chain n-3 fatty acids in man decreases expression of the interleukin-2 receptor (CD25) on mitogen-stimulated lymphocytes from patients with inflammatory skin diseases

Abstract T-cell activation and cytokine production play an important role in several chronic inflammatory diseases. Because n-3 fatty acids exert beneficial effects on the clinical state of some of these diseases, we examined the effect of dietary supplementation of n-3 fatty acids on T-cell proliferation, expression of CD25 (interleukin-2 receptor alpha-chain), secretion of interleukin-2, interleukin-6 and tumour necrosis factor from T-cells from patients with psoriasis and atopic dermatitis. During 4 months, 21 patients supplied 6 g of highly concentrated ethyl esters of EPA and DHA in gelatin capsules daily to their diet. In the control group 20 patients supplied 6 g per day of corn oil in gelatin capsules to their diet. Eicosapentaenoic acid (20:5, n-3) of serum phospholipids increased from 14 (min 4-max 42) to 81 (min 59-max 144) mg l^-1 (P < 0·01) in patients with atopic dermatitis receiving n-3 fatty acids, and from 25 (min 7-max 66) to 74 (min 46-max 142) mg l^-1 (P < 0·01) in patients with psoriasis, whereas docosahexaenoic acid (22:6, n-3) increased from 65 (min 46-max 120) to 92 (min 54-max 121) mg l^-1 (P < 0·05) and from 81 (min 38-max 122) to 92 (min 63-max 169) mg l^-1 (NS) in atopic and psoriatic patients, respectively. The changes in the serum phospholipid fatty acid profile in the groups receiving n-3 fatty acids, correlate to the dietary intake of corresponding fatty acids. There was no significant change in the fatty acid pattern of serum phospholipids in the corn oil group before and after supplementation. Mitogen-induced secretion of interleukin-6 was significantly higher in patients with psoriasis compared to patients with atopic dermatitis, whereas the secretion of interleukin-2, tumour necrosis factor, PHA-induced T-cell proliferation and expression of CD25 on lymphocytes were similar in the two groups of patients. Patients receiving supplementation of n-3 fatty acids decreased significantly the percentage of CD25 positive lymphocytes from 40·5 before start to 35·5 (P < 0·05) after the trial. The patients who received corn oil increased the level of tumour necrosis factor from 1095 pg ml^-1 before start to 1536 pg ml^-1 after the trial (P < 0·05). In conclusion, dietary intake of very long-chain n-3 fatty acids may suppress the expression of CD25 positive lymphocytes, which may partly account for the anti-inflammatory effect exerted by these fatty acids.     

The Effect of Insulin on the Intracellular Distribution of 14(R,S)-[18F]Fluoro-6-thia-heptadecanoic Acid in Rats

Purpose The aim of this study was to determine the effect of hyperinsulinemia on myocardial and hepatic distribution and metabolism of 14(R,S)-[¹⁸F]fluoro-6-thia-heptadecanoic acid ([¹⁸F]FTHA).Procedures Mitochondrial retention and intracellular lipid incorporation of [¹⁸F]FTHA were compared to that of [¹⁴C]-2-bromopalmitate or [¹⁴C]palmitate during hyperinsulinemic clamp vs. saline infusion in male Wistar rats.Results Mitochondrial ¹⁸F activity was increased in the heart (1.7 ± 0.4 vs. 0.5 ± 0.1% ID/g, P < 0.05), whereas it was reduced in the liver (1.1 ± 0.3 vs. 1.8 ± 0.4% ID/g, P < 0.05) during insulin vs. saline infusion, respectively. Mitochondrial [¹⁴C]-2-bromopalmitate activity was affected by insulin in a similar way in both tissues. The fractional esterification of [¹⁸F]FTHA into triglycerides was impaired compared to [¹⁴C]palmitate in both tissues, and [¹⁸F]FTHA was insensitive to the shift of esterification of fatty acids into complex lipids in response to insulin.Conclusions [¹⁸F]FTHA is sensitive to insulin-induced modifications of free fatty acid oxidative metabolism in rats but is insensitive to changes in nonoxidative fatty acid metabolism.     

Efcts of chronic ethanol feeding on serum lipoprotein metabolism in the rat

In rats, chronic ethanol feeding was found to enhance the postprandial hyperlipemia and to increase the incorporation of dietary palmitic acid-³H and intravenously injected L-lysine-¹⁴C into serum lipoproteins. The main increases of total amount, labeling, and specific activity of lipid and protein occurred in the d < 1.019 lipoprotein fraction. Fat absorption and the clearance of injected chylomicrons were not affected by ethanol feeding. Blocking of lipoprotein and chylomicron removal with Triton did not prevent the action of ethanol on serum lipids, indicating that the ethanol effect is not likely due to defective removal of lipids from the circulation. Ethanol enhanced the incorporation of chylomicron fatty acids into newly synthetized very low density lipoproteins, as shown by an increased reappearance of the fatty acid label into the lipids of this fraction after injection of palmitate-¹⁴C/glycerol-³H doubly labeled chylomicrons. These results indicate that alcoholic hyperlipemia is due, at least in part, to an increase in newly synthetized lipoproteins. The hyperlipemia produced by ethanol was accompanied by hepatic steatosis. The simultaneous production of fatty liver and hyperlipemia makes it unlikely that defective lipoprotein synthesis or secretion is a primary mechanism for the pathogenesis of the alcoholic fatty liver.     

Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption

The role of nonchylomicron very low density lipoproteins (VLDL, S(f) 20-400) in the transport of triglyceride and cholesterol was studied during lipid absorption. Various long chain fatty acids were infused intraduodenally in the form of mixed fatty acid-mono-olein-taurocholate micelles; control animals received saline or taurocholate.As compared with controls, all fatty acids (palmitic, oleic, linoleic) resulted in significant increases in chylomicron (S(f) > 400) triglyceride. In addition, palmitic acid resulted in a twofold increase in VLDL triglyceride, whereas with the absorption of oleic or linoleic acid VLDL triglyceride did not change significantly. Differences in triglyceride fatty acid composition between chylomicrons and VLDL were observed during lipid absorption.Although the absolute amount of endogenous cholesterol in intestinal lymph was not significantly affected by lipid absorption under these conditions, its lipoprotein distribution differed substantially among the lipid-infused groups. During palmitate absorption, VLDL cholesterol was similar to that in the taurocholate-infused controls, and was equal to chylomicron cholesterol. In contrast, during oleate and linoleate absorption the VLDL cholesterol fell markedly, and was less than half of the chylomicron cholesterol in these groups. The half-time of plasma survival of VLDL cholesterol-(14)C was found to be twice that of chylomicron cholesterol-(14)C.These studies demonstrate that dietary long chain fatty acids differ significantly in their effects upon the transport of triglyceride and cholesterol by lipoproteins of rat intestinal lymph. These findings, together with the observed differences in rates of removal of chylomicrons and VLDL from plasma, suggest that variations in lipoprotein production at the intestinal level may be reflected in differences in the subsequent metabolism of absorbed dietary and endogenous lipids.     

Effect of acute hyperinsulinemia on fatty acid composition of serum lipids in non-insulin-dependent diabetics and healthy men.

The fatty acid pattern of serum phospholipids, cholesteryl esters, triglycerides and free fatty acids was measured before and after a 5-h two-step euglycemic hyperinsulinemic clamp (75 and 1400 microU/ml) in 21 non-insulin-dependent diabetics and 14 age-, weight-, and sex-matched healthy controls. Acute hyperinsulinemia was associated with a statistically significant increase in essential fatty acid and a decrease in non-essential fatty acid contents in triglycerides while the levels of serum triglycerides and free fatty acids dropped in both groups. The fatty acid composition of phospholipids and cholesteryl esters remained unchanged as did the levels of serum phospholipids, total cholesterol and HDL cholesterol.     

Hyperpolarized 13C‐labelled anhydrides as DNP precursors of metabolic MRI agents

The extraordinary enhancement of the nuclear magnetic resonance (NMR) signal that can be obtained by dynamic nuclear polarization (DNP) techniques is prompting new avenues of research based on the in vivo detection of metabolic abnormalities associated with the onset and progression of human diseases. ¹³C‐labelled short‐chain fatty acids appear to be interesting candidates for this novel class of metabolic‐active contrast agents (MCAs), as they have been shown to report on metabolic differences between healthy and ischaemic tissues in mice. In spite of their promising biological efficacy, the formulations of short‐chain fatty acids that fulfil the many technical constraints of the DNP procedure, as it is today, may limit their clinical potential. New solutions have been sought to circumvent technology‐related challenges and facilitate clinical translation of these molecules. In particular, it has been shown that, by using symmetric anhydrides as chemical precursors for short‐chain fatty acids, no glass‐forming additives are needed in the DNP formulations. Furthermore, novel esterified trityl radicals and lipophilic gadolinium complexes allow easy removal of the polarization‐promoting additives at the end of the DNP process. By applying the three concepts reported, we have succeeded in preparing aqueous formulations of short‐chain fatty acids for pharmaceutical use that have favourable properties compared with those obtained from current procedures. The use of organic derivatives as chemical precursors of the MCA of interest appears to be a generally valid concept, not restricted to symmetric anhydrides of fatty acids, which can markedly improve the clinical potential of other ¹³C‐labelled compounds. Copyright © 2012 John Wiley & Sons, Ltd.     

Does Omega-3 Fatty Acid Supplementation Have Favorable Effects on the Lipid Profile in Postmenopausal Women? A Systematic Review and Dose–response Meta-analysis of Randomized Controlled Trials

PurposeMenopause is associated with disturbances in the metabolism of lipids. Moreover, during the postmenopausal period, female subjects are more prone to develop dyslipidemia. Omega-3 fatty acids, which exert cardioprotective, anti-inflammatory, and lipid-lowering actions, are commonly recommended in postmenopausal women. However, their effect on serum lipids in this population remains unclear. This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to clarify this research question.MethodsWe systematically searched the Web of Science, Scopus, PubMed/MEDLINE, and EMBASE databases from their inception until January 3, 2022. The DerSimonian and Laird random-effects model was used to combine effect sizes.FindingsOmega-3 fatty acid supplementation resulted in a decrease in triglyceride concentrations (weighted mean difference [WMD], –17.8 mg/dL; 95% CI, –26 to –9.6; P < 0.001), particularly in the RCTs that lasted ≤16 weeks (WMD, –18.6 mg/dL), when the baseline triglyceride concentrations were ≥150 mg/dL (WMD, –22.8 mg/dL), in individuals with a body mass index ≥30 kg/m² (WMD, –19.3 mg/dL), and when the dose of omega-3 fatty acids was ≥1 g/d (WMD, –21.10 mg/dL). LDL-C (WMD, 4.1 mg/dL; 95% CI, 1.80 to 6.36; P < 0.001) and HDL-C (WMD, 2.1 mg/dL; 95% CI, 0.97 to 3.2; P < 0.001) values increased. Total cholesterol levels (WMD, –0.15 mg/dL; 95% CI, –4 to 3.74; P = 0.94) remained unchanged after administration of omega-3 fatty acids.ImplicationsIn postmenopausal women, supplementation with omega-3 fatty acids resulted in a significant reduction in triglyceride concentrations and a modest elevation in HDL-C and LDL-C levels, whereas this intervention did not affect total cholesterol values.