Effects of nicotinic acid treatment on glyceride formation and lipolysis in adipose tissue of hyperlipidemic patients

Summary Thirty-one weight-stable patients with different types of hyperlipoproteinemia were treated daily with 4g nicotinic acid for 6 weeks. Effects of this therapy on adipose tissue metabolism were evaluated. By using biopsy specimens of subcutaneous adipose tissue, fatty acid and glucose incorporation into adipose tissue glycerides were measured in vitro as well as glycerol and fatty acid release, which allowed us to estimate adipose tissue lipolysis. The amount of fatty acids produced by lipolysis and thereafter utilized within adipose tissue without being released (fatty acid retention) was estimated. Fatty acid and glucose incorporation into adipose tissue, glycerol release and fatty acid retention values increased, but serum triglyceride levels decreased (allP<0.001) after nicotinic acid treatment. The change in fatty acid incorporation was positively correlated with changes in glucose incorporation into adipose tissue (r=0.53,P<0.01) and fatty acid retention (r=0.76,P<0.001). Although adipose tissue lipolysis, measured as glycerol release, increased, the lipolyzed fatty acids were retained in adipose tissue, suggesting an enhanced synthesis of glycerides both from exogenous and endogenous sources. The increase in fatty acid incorporation into adipose tissue indicates that the decrease in serum triglyceride levels produced by nicotinic acid treatment may partly be due to the fact that this drug promotes incorporation of fatty acids, derived from lipoprotein-carried triglycerides in the blood, into adipose tissue glycerides.     

A micro-method for determination of fatty acid (FIAT) and glucose (GLIAT) incorporation and lipolysis in vitro in needle biopsies of human adipose tissue.

A method for determination of fatty acid (FIAT) and glucose (GLIAT) incorporation into adipose tissue in vitro in needle biopsy specimens of human fat has been developed. 20-150 mg of subcutaneous fat is incubated in an albumin buffer containing a physiological spectrum and concentration of fatty acids and glucose. Release of glycerol and fatty acids to the incubation medium and incorporation of labelled palmitic acid and labelled glucose into extracted adipose tissue lipids are determined simultaneously. The labelled fatty acids are found in the fatty acid part and the labelled glucose only in the glycerol part of extracted diglycerides and triglycerides. These glycerides are completely recovered and indicated FIAT and GLIAT values. Methodological errors for all vaiables are about 10%. All processes increase linearly with tissue weight and incubation time. FIAT and GLIAT increase linearly with increasing concentration of a physiological spectrum of fatty acids (=constant fractional incorporation). The method is simple, and several analyses from one subject can be performed on one day with a minimum of discomfort to the patient.     

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.     

Nonsuppressible insulin-like activity (NSILA) of human serum. V. Hypoglycaemia and preferential metabolic stimulation of muscle by NSILA-S

Abstract 10 mU of NSILA-S, as determined by the fat pad assay, lowered blood glucose and free fatty acids of adrenalectomized rate for a much longer period than 10 mU of crystalline insulin. NSILA-S was not measurably inactivated by the liver during a 2 h cyclical perfusion, whereas insulin rapidly lost activity with a half-life of 42 min. 6 mU of NSILA-S injected intravenously stimulated the incorporation of [6-¹⁴C] glucose into the diaphragm of streptozotocin-diabetic rats to a much greater extent than 6 mU of insulin, whereas their effects on the incorporation of carbon 14 into the fat pad were equal. When injected intraperitoneally in maximal doses to normal rats both agents stimulated the incorporation of [U-¹⁴C] glucose into adipose tissue and diaphragm to the same extent. There was no potentiation of either agent by the other on adipose tissue in vitro, indicating that they affect the same transport site of the cell membrane. Insulin and NSILA-S influenced the metabolism of adipose tissue of fasted-refed rats in the same manner. It is concluded that i.v. injected NSILA-S is more effective in vivo than comparable doses of insulin because it is not inactivated by the liver. Furthermore, it seems to have a particular affinity to receptors of the muscle cell membrane. This may be an additional factor in protecting it from inactivation by other tissues.     

Effects of nicotinic acid on glucose tolerance and glucose incorporation into adipose tissue in hypertriglyceridaemia.

Nicotinic acid 4 g daily was given to 28 weight-stable hypertriglyceridaemic patients. The aim was to study its effects on serum lipoprotein lipid levels, intravenous glucose tolerance (k-values) and glucose incorporation into subcutaneous adipose tissue (GLIAT) in vitro. The investigations were performed prior to the nicotinic acid therapy, after 6 weeks, and 6 months of drug treatment. Fasting blood glucose levels increased by 13%, whereas k-values fell by 26% after the nicotinic acid treatment. Decrease in k-values was predicted from the initial k-values (R2-value = 0.76). GLIAT increased by 76%, while in the subgroup of eight patients, treated for 6 months with nicotinic acid, GLIAT increased by 331%. The changes in k-values and GLIAT were not significantly interrelated. Serum triglyceride levels were strongly decreased. The most likely explanation for the decrease in intravenous glucose tolerance is that nicotinic acid stimulates glucose output from the liver and that this effect outweighs the stimulating effects of the drug on glucose utilization in extrahepatic tissues. The latter is reflected by the increased uptake of glucose in adipose tissue. A stimulated GLIAT, reflecting formation of alpha-glycerophosphate in adipose tissue, might contribute to the reduction of serum triglyceride levels induced by nicotinic acid, since alpha-glycerophosphate is the acceptor of fatty acids assumed to be liberated from circulating triglycerides by lipoprotein lipase.     

Altered lipid metabolism in human platelets after primary aggregation

Thrombin and poly-l-lysine alter the incorporation of acetate, glycerol, and fatty acids into the lipids of washed human platelets. Both aggregating agents decrease the incorporation of acetate into all lipid classes other than free fatty acids. Similarly, glycerol incorporation into complex lipids is impaired by both thrombin and polylysine. Thrombin caused marked depression of the incorporation of palmitic acid into both lecithin and triglycerides. By contrast it enhanced the incorporation of oleic acid into lecithin, but not into triglycerides. The data suggest that the process of primary platelet aggregation is associated with a defect in the assembly of complex lipids.     

Triglyceride synthesis in human subcutaneous adipose tissue cells of different size

Abstract Human adipose tissue fat cells, liberated by eollagenase treatment, were separated into different sizes with a technique utilizing the differences in flotation rates of large and small fat cells in a physiological medium. — Incubation of fat cells after treatment with collagenase caused a pronounced breakage of fat cells. Therefore only incorporation of radioactivity from l-¹⁴C-glucose into triglyceride but not into carbon dioxide could be measured in separated fat cells. When collagenase-liberated fat cells were incubated with radioactive glucose, radioactivity in the triglycerides increased with fat cell diameter in the remaining intact fat cells. When intact adipose tissue was incubated with radioactive glucose and then subjected to collagenase treatment, followed by separation of fat cells into different fat cell size classes, the same phenomenon was observed, namely a significant positive correlation between fat cell size and incorporation of radioactivity from glucose into triglycerides in adipose tissue with a wide range of fat cell diameters. Insulin response was small and varying. The dependence of triglyceride synthesis on fat cell size varied in different adipose tissue samples.     

The Monoglyceride Pathway of Fat Absorption in Man

The absorption of fat was studied in five male subjects with cannulation of the thoracic duct in the neck by the administration of doubly labeled monoglycerides, or triglyceride as well as labeled free glycerol or labeled free oleic acid, by gastric or duodenal intubation.Total recoveries of the administered glyceride radioactivity from the lymph lipids ranged from 35 to 53% for the glycerol label (tritium) and from 35 to 57% for the fatty acid label ((14)C). The recovery of administered radioactive free glycerol in lymph lipids was only 4.1%, even when given in mixture with bile salts, fatty acid, and monoglyceride.A comparison of the isotope ratios of the two components (glycerol and fatty acid) of the lymph glycerides with the ratios of these components of the original meal glyceride showed little change during the initial period of fat absorption, indicating that the doubly labeled monoglycerides passed into the lymph intact. During the later part of the period of major fat absorption, the ratios in lymph lipids changed due to loss of glycerol representation, indicating monoglyceride hydrolysis and portal venous diversion of free glycerol.Confirmation of the intact nature of 2-monoglyceride during absorption was made by analyzing the amount and position of the labeled fatty acid in the lymph triglycerides. The percentage of labeled fatty acid in the various positions of the lymph triglycerides was virtually identical with that of the meal during the initial period of fat absorption and then changed reflecting isomerization of fatty acids and subsequent complete hydrolysis of the glycerides.The 2-monoglyceride pathway appears to be the major route of fat absorption for man during normal digestion and absorption of dietary triglyceride.     

Effects of acipimox, a nicotinic acid derivative, on lipolysis in human adipose tissue and on cholesterol synthesis in human jejunal mucosa

The mode of action of acipimox (5-methyl-pyrazine carboxylic acid 4-oxide), an hypotriglyceridaemic agent, was examined in human adipose tissue and intestinal mucosa. The rates of release of fatty acids and glycerol from human adipose tissue were measured in vitro. The release of fatty acids and glycerol from adipose tissue maximally stimulated by isoprenaline (10(-5) mol/l) fell by 40 and 25% respectively (P less than 0.025 and P less than 0.025) in the presence of acipimox (10(-5) mol/l). In submaximally stimulated adipose tissue (isoprenaline 10(-7) mol/l) acipimox (10(-4) mol/l) fully inhibited release of fatty acids (P less than 0.05) and glycerol (P less than 0.025) to basal rates. In unstimulated adipose tissue acipimox (10(-3) mol/l) reduced the rate of glycerol release (P less than 0.05), but not the rate of fatty acid release. Cholesterol synthesis in jejunal mucosa was measured in vitro by the incorporation of [2-14C]-acetate into sterols. Addition of cholesterol to the incubation reduced [2-14C]acetate incorporation into sterols from 8.7 +/- 2.1 (mean +/- standard error) to 3.7 +/- 1.0 pmol h-1 mg-1 of tissue (P less than 0.01). Acipimox at 10(-4)-10(-2) mmol/l had no consistent effect on cholesterol synthesis. Acipimox appears to exert its main hypolipidaemic effect by reducing lipolysis and free fatty acid flux to the liver, thereby reducing the precursor pool size of very low density lipoprotein (VLDL)-triglyceride and VLDL synthesis.     

Effects of nicotinic acid treatment on fatty acid composition of plasma lipids and adipose tissue in hyperlipidaemia.

Effects of 6-week treatment with 4 g daily of nicotinic acid on fatty acid composition in different serum lipids and in adipose tissue glycerides were studied in 31 hyperlipidemic patients. The percentages of eight fatty acids in triglycerides, phospholipids and cholesteryl esters of whole plasma as well as in subcutaneous adipose tissue glycerides were measured. Nicotinic acid treatment produced decreases in triglyceride and total cholesterol concentrations of VLDL and LDL, whereas HDL total cholesterol levels in serum increased after drug therapy, all p less than 0.01. There were reductions in the relative contents of myristic acid in plasma phospholipids (from 0.4% to 0.3%; p less than 0.05) and cholesteryl esters (from 0.9% to 0.7%; p less than 0.001). There were decreases in the percentages of stearic acid in plasma phospholipids (from 17.0% to 15.0%) and cholesteryl esters (from 1.2% to 1.0%; both p less than 0.001). The relative contents of polyunsaturated fatty acids, mainly linoleic acid, in plasma phospholipids were increased (from 32% to 33.5%; p less than 0.05). There were reductions in the linolenic acid contents of adipose tissue (from 1.5% to 1.1%) and plasma triglycerides (from 1.1% to 0.8%), both p less than 0.05, possibly indicating increased conversion of linolenic acid to prostaglandins. There was no relationship between changes in the percentages of individual fatty acids and changes in triglyceride or total cholesterol levels of whole serum and its VLDL, LDL and HDL fractions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of Reduced Myocardial Glucose Utilization During Acute Hypertriglyceridemia in Rats

Purpose  The purpose of the research is to study the effect of acute inhibition of intravascular lipolysis on myocardial substrate selection during hypertriglyceridemia using in vivo radiotracer analysis and positron emission tomography. Procedures  We induced acute hypertriglyceridemia in vivo using an intravenous infusion of Intralipid 20% (IL) without and with acute inhibition of fatty acid delivery from circulating triglycerides with injection of Triton WR-1339 (TRI) during a euglycemic–hyperinsulinemic clamp in Wistar rats. We determined the effect of TRI on myocardial uptake of circulating triglycerides and free fatty acids using intravenous injection of [³H]-triolein and [¹⁴C]-bromopalmitate, respectively. Myocardial blood flow, oxidative metabolism, and metabolic rate of glucose (MMRG) were determined using micro-positron emission tomography (μPET) with [¹³N]-ammonia, [¹¹C]-acetate, and 2-deoxy-2-[F-18]fluoro-d-glucose (FDG). Results  TRI reduced myocardial incorporation of [³H]-triolein but not [¹⁴C]-bromopalmitate showing that it selectively reduces myocardial fatty acid delivery from circulating triglycerides but not from free fatty acids. IL reduced myocardial blood flow and MMRG by 37% and 56%, respectively, but did not affect myocardial oxidative metabolism. TRI did not abolish the effect of IL on myocardial blood flow and MMRG. Conclusions  Hypertriglyceridemia acutely reduces myocardial blood flow and MMRG in rats, but this effect is not explained by increased myocardial fatty acid delivery through intravascular triglyceride lipolysis.     

Myocardial Lipid and Carbohydrate Metabolism in Healthy, Fasting Men at Rest: Studies During Continuous Infusion of 3H-Palmitate

Abstract Myocardial metabolism of lipid and carbohydrate substrates was studied in 17 healthy men at rest by measuring the arterial-coronary sinus [(a—cs)] concentration differences. A continuous intravenous infusion of albumin-bound ³H-palmitate was given to provide a tracer for the plasma free fatty acids (FFA) and to produce endogenous labelling of plasma triglycerides (TG). A statistically significant positive (a—cs) difference in triglyceride (TG) concentration was detected in 10 of the 17 subjects and averaged 18±4 (SEM) μmol/1 plasma for the 17 subjects. This was 1.0% of the average arterial TG concentration. A significant positive (a—cs) difference in TG radioactivity was found in 12 of the 17 subjects but it was not possible to quantitate myocardial TG extraction from these radioisotope data. Myocardial extraction of FFA based on the radiopalmitate data was on average 39% greater than the extraction of FFA measured chemically. This was interpreted as indicating an efflux of unlabelled fatty acids into the coronary sinus, most probably from a glyceride pool within the myocardium. The finding that this efflux of fatty acids was not accompanied by free glycerol suggested either that the fatty acids were derived from partial hydrolysis of glycerides, or that glycerol was metabolised within the myocardium. Seven of the subjects had significant, positive (a—cs) differences in free glycerol concentration suggesting that the human heart is capable of metabolising glycerol. There were significant, negative linear correlations between arterial FFA concentration and myocardial extraction of glucose, lactate and pyruvate with significant efflux of pyruvate from the heart at higher FFA concentrations. These findings suggested that FFA can decrease glucose extraction by the human heart and that one possible mechanism for this may be the inhibition of pyruvate dehydrogenase. The average (±SEM) oxygen extraction ratios (OERs) for the substrates were: TG 16±4%; FFA 48±3%; glucose 20±3%; lactate 8±2%; pyruvate 1±0.3%. The total OER for these substrates averaged 97% suggesting that in the resting, fasting, state there is little change in the total energy content of endogenous myocardial substrate pools.     

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.     

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.     

Glucose metabolism in human adipose tissue studied by 13C‐glucose and microdialysis

Objective. Microdialysis can be used to monitor carbohydrate metabolism and lipolysis in adipose tissue. This method, however, does not discriminate between local metabolite production and delivery from other tissues. Our aim was to study glucose metabolism by direct delivery of ¹³C‐labelled glucose into adipose tissue by microdialysis. Material and methods. Seven healthy adults were studied after an overnight fast. In three of them the effect of physical activity on glucose metabolism was tested. Microdialysis catheters were introduced into abdominal adipose tissue and 25?mM ¹³C‐labelled glucose was added to the perfusion fluid. An extraction procedure for separating lactic acid from glucose and glycerol in the microdialysate samples was developed. After derivatization, the ¹³C enrichment of the compounds was analysed by gas chromatography‐mass spectrometry. Results.¹³C‐labelled lactate was detected in the first 15‐min eluate fraction following that in which ¹³C‐glucose had reached the microdialysis probe. In the different subjects, 22–35?% of adipose tissue lactate was produced locally. During exercise there was an increase in the lactate concentration and a decrease in ¹³C enrichment of lactate. Although lactate production in the adipose tissue increased during exercise, most adipose tissue lactate resulted from inflow. The administered ¹³C‐labelled glucose also rapidly converted to ¹³C‐glycerol. The ¹³C enrichment of glycerol was lower than that of lactate. During exercise the ¹³C enrichment of glycerol increased, indicating that newly synthesized depot fat was preferentially hydrolysed during physical activity. Conclusions. Metabolism of glucose to lactate and glycerol in subcutaneous adipose tissue is a rapid process that can be monitored in vivo by administration of stable isotope labelled glucose into the microdialysis probe. In adults at rest about one‐fourth of adipose tissue lactate is produced locally.     

Removal of Exogenous Plasma Triglycerides in Forearm Muscle and Subcutaneous Tissue of Hyper-and Normotriglyceridaemic Men

Absolute arterio-venous removal and fractional removal of blood-borne exogenous triglyceride particles by skeletal and subcutaneous tissues were determined in eight normotriglyceridaemic and six hypertriglyceridaemic men. Estimations were made by simultaneously sampling blood from catheters inserted into a brachial artery, and in the distal direction, into a superficial and deep vein, draining subcutaneous tissue and skeletal muscle respectively. During the infusion of the fat emulsion Intralipid^R for 3 hours steady arterial concentrations of exogenous TG particles were found, indicating first order kinetics. In all subjects absolute arterio-venous and fractional removal of triglycerides were about twice as high in skeletal muscle as in subcutaneous tissue. In skeletal muscle the fractional removal and absolute removal were significantly higher in normotriglyceridaemic than in hypertriglyceridaemic subjects (p < 0.001). No decrease in removal with time was observed, which would have suggested saturation of removal sites. Mean fractional removal in skeletal muscle was significantly correlated with the k2 value determined by an intravenous fat tolerance test before the infusion study (r = 0.61, p < 0.05). In subcutaneous tissue fractional removal was also significantly higher in normotriglyceridaemic subjects (p < 0.05). The results suggest that in both skeletal muscle and subcutaneous tissue the removal system is impaired in hypertriglyceridaemic subjects. This finding supports the concept that a decreased elimination capacity in these tissues may partly account for triglyceride elevation in hypertriglyceridaemic subjects.     

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.     

Fatty Acid Transport and Incorporation into Human Erythrocytes In Vitro

When human erythrocytes were incubated in vitro with (14)C-labeled free fatty acids bound to serum albumin, labeled fatty acids were incorporated into erythrocyte triglycerides and phospholipids. The first step in this reaction was the transfer of free fatty acids from the albumin to the cells. This transfer was rapid and reversible. The acids were distributed between albumin and cells according to the relative quantities of albumin and cells present. Each acid had a different distribution coefficient. At equilibrium, relatively larger fractions of the stearic and palmitic acids and smaller fractions of the oleic and linoleic were associated with the cells. All these fatty acids were then slowly incorporated into phospholipids and triglycerides. The rate of incorporation of each was a function of its concentration in the cells, but larger fractions of the oleic and linoleic were incorporated than of the stearic, palmitic, myristic, or lauric. The two processes of transfer and incorporation thus had almost opposite selectivities for the different fatty acids. As a result, the fatty acids incorporated into triglycerides and phospholipids resembled in composition the fatty acids on the albumin except for moderately less stearic acid.     

Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.

Fatty acid metabolism in intestinal mucosa has been examined primarily in regard to lipid absorption. Since earlier studies suggested intestinal utilization of plasma free fatty acids (FFA), we investigated mucosal metabolism of plasma FFA in rats. Mucosal radioactivity (1 per cent of administered) was maximal 2 min after i.v. [14C]palmitate. Of mucosal 14C, 42 percent was in water-soluble metabolites, including CO2 and ketoacids, 28 percent in phospholipids, and only 16 per cent in triglycerides. The specific activity of mucosal triglyceride fatty acids (TGFA) was 11 times that of serum TGFA, confirming in situ synthesis. Double isotope experiments showed marked differences in the metabolism of fatty acids entering mucosa simultaneously from lumen and plasma. Whereas luminal fatty acids were chiefly esterified to triglyceride, plasma FFA were preferentially oxidized and incorporated into phospholipids. Crypts did not differ from villi, indicating that intestinal metabolism of plasma FFA is related to their site of entry into epithelial cells. Mucosal metabolism of i.v. [14C]palmitate was minimally affected by glucose administration. However, intraduodenal isocaloric ethanol inhibited mucosal oxidation of FFA by 60 per cent, and increased incorporation into triglycerides nearly twofold. During lipid absorption, mucosal uptake of plasma FFA doubled and incorporation into intestinal lymph triglycerides was increased sixfold. These studies demonstrate an intracellular compartmentation of fatty acids in the intestinal epithelium. In contrast to absorbed luminal fatty acids, plasma FFA in the fasting state are both an energy source and a substrate for the synthesis of tissue phospholipid. The fasting contribution of plasma FFA to mucosal and lymph triglyceride is minimal, but it increases during ethanol administration and fat absorption.     

The incorporation of acetate-1-C14 into cholesterol and fatty acids by surviving tissues of normal and scorbutic guinea pigs

The synthesis of cholesterol and fatty acids from acetate-l-C¹⁴ by the isolated liver, adrenal, and aorta of scorbutic and pair-fed control guinea pigs has been studied. It was found that ascorbic acid deficiency does not affect the rate of incorporation of C¹⁴-acetate into cholesterol and fatty acids by the tissues investigated, under our experimental conditions. The relatively high metabolic activity of the artery with regard to cholesterogenesis and lipogenesis was noted. The elevation of serum cholesterol and hexosamine in scurvy has been confirmed.