The effect of sex on the quantity and properties of the very low density lipoprotein secreted by the liver in vitro.

Livers from normally fed male and female rats were perfused in vitro with different amounts of oleate, and the production and properties of the very low density lipoprotein (VLDL) were studied. The mobility of the VLDL in the zonal ultracentrifuge was dependent on the uptake of free fatty acid and on the sex of the animal from which the liver was obtained. A higher proportion of the VLDL secreted by livers from females displayed a more rapid mobility in the zonal ultracentrifuge and, in addition, contained less phospholipid and cholesterol per mole triglyceride than the VLDL from the male, suggestive of larger size of the VLDL secreted by livers from the female rats. Such differences were diminished when the VLDL was compared at equal output of triglyceride but unequal uptake of free fatty acid. These data suggest that the properties of the VLDL are only secondarily modulated by sex, and primarily result from differences in the capacities of livers from either male or female rats to synthesize triglyceride for transport as VLDL. The quantity of triglyceride secreted, regardless of sex, may be an important determinant of both size and number of the VLDL particles. The incorporation of endogenous hepatic fatty acid into VLDL triglyceride was diminished in livers from both sexes by increased uptake of oleate. The greater output of VLDL triglyceride by livers from female animals was dependent on both exogenous and endogenous fatty acids when relatively small quantities of exogenous oleate were available for uptake by the liver. The proportion of palmitate and oleate in the phospholipid of the VLDL secreted by livers from male rats decreased and the content of arachidonate increased with increasing uptake of oleate; no differences were observed in the composition of the phospholipid fatty acids among the various experimental female groups, although these contained more stearate and less oleate and linoleate compared to the male groups. The change of fatty acid composition of the VLDL phospholipid may reflect inclusion of specific types of phospholipid in the VLDL structure for transport of triglyceride from the liver under particular conditions.     

Secretion and uptake of nascent hepatic very low density lipoprotein by perfused livers from fed and fasted rats

Livers from fed or 24-hr fasted male rats were perfused in a recycling system. VLDL labeled with [1-14C]oleate (95% in triglyceride), produced in separate perfusions of livers from fed rats, was added to the medium as a pulse. Uptake of VLDL 14C-labeled triglyceride by livers from fasted rats was less than that from fed rats regardless of addition of oleate. During the interval in which radioactive triglyceride was taken up, the mass of triglyceride in the medium increased, indicative of the synthesis and net secretion of triglycerides. The rates of secretion of VLDL and uptake of VLDL were both more rapid in livers from fed rats in comparison to those from fasted animals. It was calculated that about 50% of the triglyceride synthesized and secreted by the liver was taken back by livers from fed rats. The VLDL from livers of fasted rats did not contain any apoE detectable by SDS gel electrophoresis or by radioimmunoassay when no fatty acid or 166 mumol of oleic acid was infused. In contrast, apoE comprised 6% of the VLDL apoprotein derived from perfusion of livers from fed animals in the absence of added fatty acid, and 20% when the fed livers were infused with 166 mumol of oleic acid. However, the net output (accumulation) of apoE by fasted liver was only two-thirds that from fed livers. When lipoprotein-free rat plasma containing apoE (4 mg/dl) was used in place of bovine serum albumin, the VLDL secreted by livers from either fed or fasted rats contained apoE and was taken up to a similar extent by such livers. These data suggested that the apoE of the d greater than 1.21 g/ml fraction was transferred to newly secreted VLDL which then stimulated uptake of the VLDL by livers from fasted rats. With further stimulation of secretion of VLDL triglyceride by infusion of 332 mumol of oleic acid/hr, the percent of apoE in the VLDL secreted by livers from fasted rats increased to 20%, which was similar to that of the VLDL produced by livers from fed rats when either 166 or 332 mumol/hr was infused. These data suggest a relationship between rates of hepatic secretion of VLDL (TG) and apoE, and the association of apoE with the secreted VLDL. During fasting, reduced secretion of both VLDL and apoE resulted in a VLDL particle that was considerably diminished in content of apoE and, therefore, that would be taken up by the liver at a reduced rate, in comparison to that observed in the fed animal.     

Effect of essential fatty acid deficiency on release of triglycerides by the perfused rat liver

Studies are reported on release of triglycerides during perfusion of livers of male Sprague-Dawley rats fed a fat-free diet or diets containing hydrogenated coconut oil or corn oil. Perfusions were carried out with Krebs-Ringer bicarbonate buffer containing albumin with and without infusion of oleate or linoleate. Infusion with sodium oleate or linoleate caused an accumulation of triglycerides in the livers of the corn oil-fed animals and stimulated the release of triglycerides into the perfusing medium. In similar experiments with essential fatty acid-deficient animals, which were fed fat-free diets or diets containing hydrogenated coconut oil, there was no increase in secretion of triglycerides into the perfusate, and the amount of triglyceride which accumulated in the liver was greater than in the livers of the control (corn oil-fed) animals. Tracer experiments with oleate-1-(14)C or linoleate-1-(14)C also showed that with livers of essential fatty acid-deficient animals, secretion of triglyceride into the perfusate was not stimulated by infusion of fatty acids into the perfusing medium. It is concluded that impairment of the secretion of triglycerides is a factor in the accumulation of fat in the livers of essential fatty acid-deficient animals.     

Fatty acid metabolism and lipid secretion by perfused livers from rats fed laboratory stock and sucrose-rich diets

To assess the possible role of altered hepatic processing of free fatty acids in dietary sucrose-induced accumulation of triglyceride in the liver and blood plasma, livers from rats fed commercial laboratory stock and high sucrose diets were perfused both with and without oleic acid substrate. Consumption of the sucrose diet exerted a multiplicity of effects on oleic acid metabolism, characterized by decreased conversion to both ketone bodies and carbon dioxide, increased esterification into liver triglyceride, and increased secretion in triglyceride-rich lipoproteins. During the infusion of oleic acid, livers from sucrose-fed rats also exhibited decreased ketogenesis, and increased secretion of triglyceride from endogenous sources. Since oleic acid uptake from the perfusion medium was identical in both groups, the observed effects of sucrose feeding are ascribed to altered rates of intracellular metabolic processes. Mass and radiochemical analyses of perfusate ketone bodies and triglycerides were indicative of greater mobilization of triglycerides from hepatocellular lipid droplets in the livers from sucrose-fed rats. These livers contained more triglyceride and secreted more triglyceride even in the absence of infused oleic acid. In summary, the sucrose-rich diet increased the esterification:oxidation ratio of intracellular free fatty acids derived from both the circulation and endogenous sources within the hepatocyte. In response, secretion of triglyceride-rich lipoproteins by the liver and deposition of triglyceride within the liver were promoted. It is concluded that alterations in the processing of free fatty acids by the liver contribute significantly to the liver and plasma triglyceride accumulation following sucrose consumption.     

Comparison of metabolism of free fatty acid by isolated perfused livers from male and female rats.

Livers from normal, fed male and female rats were perfused with different amounts of [1-14C]oleate under steady state conditions, and the rates of uptake and utilization of free fatty acid (FFA) were measured. The uptake of FFA by livers from either male or female rats was proportional to the concentration of FFA in the medium. The rate of uptake of FFA, per g of liver, by livers from female rats exceeded that of the males for the same amount of FFA infused. The incorporation by the liver of exogenous oleic acid into triglyceride, phospholipid, and oxidation products was proportional to the uptake of FFA. Livers from female rats incorporated more oleate into triglyceride (TG) and less into phospholipid (PL) and oxidation products than did livers from male animals. Livers from female rats secreted more TG than did livers from male animals when infused with equal quantities of oleate. The incorporation of endogenous fatty acid into TG of the perfusate was inhibite) by exogenous oleate. At low concentrations of perfusate FFA, however, endogenous fatty acids contributed substantially to the increased output of TG by livers from female animals. Production of 14CO2 and radioactive ketone bodies increased with increasing uptake of FFA. The partition of oleate between oxidative pathways (CO2 production and ketogenesis) was modified by the availability of the fatty acid substrate with livers from either sex. The percent incorporation of radioactivity into CO2 reached a maximum, whereas incorporation into ketone bodies continued to increase. The output of ketone bodies was dependent on the uptake of FFA, and output by livers from female animals was less than by livers from male rats. The increase in rate of ketogenesis was dependent on the influx of exogenous FFA, while ketogenesis from endogenous sources remained relatively stable. The output of glucose by the liver increased with the uptake of FFA, but no difference due to sex was observed. The output of urea by livers from male rats was unaffected by oleate, while the output of urea by livers from females decreased as the uptake of FFA increased. A major conclusion to be derived from this work is that oleate is not metabolized identically by livers from the two sexes, but rather, per gram of liver, livers from female rats take up and esterify more fatty acid to TG and oxidize less than do livers from male animals; livers from female animals synthesize and secrete more triglyceride than do livers from male animals when provided with equal quantities of free fatty acid.     

Maternal plasma triglycerides as a source of fetal fatty acids.

The transfer of plasma triglyceride fatty acids from mother to fetus was studied in rats. Following i.v. injection of labelled chylomicron and very low density lipoprotein (VLDL) triglycerides into the mother, the time courses of the plasma triglycerides, free fatty acids, and fetal radioactivity were determined. The data were analysed using a mathematical model. From the results the following conclusions were drawn: To cover the need of fetal fatty acids, the placenta utilizes only VLDL triglycerides but not chylomicron triglycerides. Comparison of the amount of VLDL triglyceride fatty acids (0.04 micromoles/min/litter) and of maternal plasma free fatty acids (0.08 micronmoles/min/litter) transferred into the fetus indicates that the maternal plasma triglycerides are a source of fetal fatty acids, that cannot be neglected.     

Triglyceride Release and Fatty Acid Oxidation by the Perfused Liver of Rats Fed a Low Protein Diet

Livers of growing rats fed a 5 or 20 protein calories percent (PC %) diet containing purified whole egg protein for three weeks were perfused in situ and the release of triglycerides (TG) and the oxidation of fatty acid by the liver alone were estimated by infusing palmitic acid-l-¹⁴C to the perfusion medium.

The release of TG from the liver of the 5 PC% group was significantly lower in both unfractionated perfusate plasma and perfusate plasma very low density lipoprotein (VLDL) than that of the 20 PC% group, whereas the content of liver TG of the 5 PC% group was higher than that of the 20 PC% group. Significantly lower radioactivity appeared in TG of both unfractionated perfusate plasma and perfusate plasma VLDL of the 5 PC% group than that of the 20 PC% group, while total radioactivity of liver TG was higher in the 5 PC% group than in the 20 PC% group. The ¹⁴CO₂ production in the perfused liver of the 5 PC% group increased gradually with time rather than decreased in comparison with that of the 20 PC% group.

These findings suggest that a major factor responsible for the liver lipid accumulation in rats fed the low protein diet is not an impaired fatty acid oxidation in the liver but an impaired secretion of TG from the liver.     

Utilization of ascites plasma very low density lipoprotein triglycerides by Ehrlich cells

Much of the lipid present in the ascites plasma in which Ehrlich cells grow is contained in very low density lipoproteins (VLDL). Chemical measurements indicated that triglycerides were taken up by the cells during in vitro incubation with ascites VLDL. When tracer amounts of radioactive triolein were incorporated into the ascites VLDL, the percentage uptakes of glyceryl tri[1-(14)C]oleate and triglycerides measured chemically were similar. The cells also took up [2-(3)H]glyceryl trioleate that was added to VLDL, but the percentage of available (3)H recovered in the cell lipids was 30-40% less than that of (1 4)C from glyceryl tri[1-(1 4)C]oleate. This difference was accounted for by water-soluble (3)H that accumulated in the incubation medium, suggesting that extensive hydrolysis accompanied the uptake of VLDL triglycerides. Radioactive fatty acids derived from the VLDL triglycerides were incorporated into cell phospholipids, glycerides, and free fatty acids, and they also were oxidized to CO(2). Triglyceride utilization increased as the VLDL concentration was raised. These results suggest that one function of the ascites plasma VLDL may be to supply fatty acid to the Ehrlich cells and that the availability of fatty acid to this tumor is determined in part by the ascites plasma VLDL concentration. Although Ehrlich cells incorporate almost no free glycerol into triglycerides, considerable amounts of [2-(3)H]glyceryl trioleate radioactivity were recovered in cell triglycerides. This indicates that at least some VLDL triglycerides were taken up intact. The net uptake of VLDL protein and cholesterol was very small relative to the triglyceride uptake, suggesting that intact triglycerides are transferred from the ascites VLDL to the Ehrlich cells and that hydrolysis occurs after the triglyceride is associated with the cells.     

Uptake and metabolism of circulating chylomicron triglyceride by rabbit aorta

To determine if chylomicron triglycerides are taken up and metabolized by the arterial wall, rabbit abdominal aortas were perfused in situ for various times up to 2 hr with blood-buffer containing isotopically labeled substrates. Labeled chylomicrons were obtained by feeding [(3)H]palmitic acid or [(3)H]glyceryl trioleate to rats and rabbits with cannulated thoracic ducts. After aortic perfusion with these chylomicrons, more than 85% of aortic lipid ester radioactivity was in triglyceride; when labeled glycerol or palmitic acid was perfused, most aortic ester lipid radioactivity was in diglycerides and phospholipids. This indicated that, during perfusion with chylomicrons, intact triglyceride molecules were taken up by aorta. The rate of triglyceride fatty acid uptake by the inner avascular segment approached maximal values at low concentrations of perfusate triglyceride fatty acids (2 mm), whereas uptake in the outer capillary perfused segment increased with increasing triglyceride fatty acid concentration (0.4-25 mm). By double-radioisotope techniques it was shown that aortic free fatty acid was derived from both perfusate free fatty acids and from hydrolysis of lipoprotein glycerides within the aortic wall. Uptake of chylomicron triglyceride by perfused aorta was independent of triglyceride hydrolysis, which was quantitatively small.     

Splanchnic and hepatic triglyceride secretion during hypercaloric intravenous glucose infusion in conscious swine.

We have validated a radiochemical technique for measuring the rate of secretion of plasma triglycerides from the liver and/or splanchnic region during the consumption of glucose under isotopic steady-state conditions. Values obtained with this technique correlated closely with those based on transhepatic or transsplanchnic chemical gradients (r = 0.95). Likewise, values for secretion of triglycerides obtained with the radiochemical technique correlated closely with those obtained for extrahepatic or extrasplanchnic triglyceride clearance. Values for mean net splanchnic and hepatic secretion of plasma triglyceride fatty acids, transported essentially in very low density lipoproteins, were 1.9 and 2.0 mumoles/min.kg body wt0.75, respectively, about one-half of the rate of transport of free fatty acids. However, the fraction of triglyceride fatty acids of plasma very low density lipoproteins that was derived from plasma free fatty acids averaged 9% and that derived from glucose, though increasing with time, reached only 2% after constant intravenous infusion of radioglucose for 5 hr. Porcine hepatic secretion of plasma triglycerides is large in the glucose-fed state, and the secreted triglyceride fatty acids evidently are derived from stored fat or glycon.     

Effects of dietary n-3 fatty acids on the composition of cholesteryl esters and triglycerides in plasma and liver perfusate of the rat

The effects of polyunsaturated fatty acids of the omega-3 family (PUFA n-3), (addition of fish oil), on the molecular composition of cholesteryl esters and triglycerides in plasma and liver perfusate of rats were studied. Rats fed a diet rich in saturated fatty acids (addition of lard) served as controls. Supplemention with PUFA n-3 not only decreases the plasma concentrations of free cholesterol, cholesteryl esters, and triglycerides, it also significantly alters the plasma composition of cholesteryl esters and triglycerides. Analyses of liver perfusate indicate a decrease in triglycerides secretion by in vitro perfused liver and reciprocal changes in relative contents of cholesteryl esters fractions with C(16) and C(20) acyl chains. This finding may be a result of chain-shortening of long-chain fatty acids probably in peroxisomal beta-oxidative system. Alterations in plasma cholesteryl esters and triglycerides composition of the fish oil group could be affected further by additional factors such as increased plasma cholesterol esterification activity and presence of triglyceride species of intestinal origin.     

Effects of glycerol on VLDL secretion by the isolated rat liver.

Stimulation of VLDL production by increasing fatty acid availability is now well established. However, a possible regulatory role of glycerol, another lipid precursor, in VLDL synthesis by the liver has not yet been substaniated. The present experiments investigate this problem using the isolated perfused rat liver. [14C] Glycerol uptake and metabolism were studied at two different glycerol concentrations: 1 mumol/perfusate (control) or 1.6 mmol/perfusate. VLDL production and lipid synthesis were investigated using [14C]leucine and several labelled fatty acids as precursors in control and glycerol-overloaded livers. Neoglycogenesis and lipogenesis from glycerol carbons are negligible in our conditions. The absolute amount of glycerol, but not the precentage, taken up by the liver, increased after raising its concentration in the perfusate. A major part of exogenous (plasmatic) glycerol was esterified with endogenous (non plasmatic) fatty acids. Incorporation of radioactive fatty acids into liver or plasma lipids was lower than in the the control group. Significant differences were observed between saturated and unsaturated fatty acids used as lipid precursors. Production of VLDL as assessed by radioactive leucine and fatty acid incorporation in the VLDL of the perfusate was depressed by glycerol. Glycerol partly inhibits the normal stimulation of VLDL production by plasmatic fatty acid overload.     

Age‐Related Changes in Fatty Acids in Obese Offspring of Streptozotocin‐Induced Diabetic Rats

Objective: The long‐term effects of fetal hyperinsulinemia, time course of changes in liver and very‐low‐density lipoprotein (VLDL) lipid levels and fatty acid compositions were investigated in obese offspring of streptozotocin‐induced mildly diabetic rats. Research Methods and Procedures: Mild hyperglycemia in pregnant rats was induced by intraperitoneal injection of streptozotocin on day 5 of gestation. Control pregnant rats were injected with citrate buffer. Liver and VLDL lipids and fatty acids were analyzed in offspring at different ages. Results: At birth, obese pups had higher VLDL triglyceride levels, saturated fatty acids, and C20:4n‐6. They also had lower C18:2n‐6 proportions in VLDL triglycerides, phospholipids, and cholesteryl esters than controls pups. In 1‐month‐old male and female obese rats, VLDL and liver lipid amounts were similar to those in their respective controls; however, high levels of C18:2n‐6 and C20:4n‐6 were noted in liver and VLDL lipids. At the age of 2 months, liver and VLDL triglyceride levels were higher in obese females than in control females. Fatty acid abnormalities seen in obese rats included low C18:3n‐3 and high C22:6n‐3 proportions in liver triglycerides and phospholipids. At the age of 3 months, obese rats, both males and females, compared with control animals, had higher VLDL and hepatic lipids with reduced C20:4n‐6 levels and polyunsaturated/saturated fatty acids ratios in hepatic and VLDL triglycerides and phospholipids. Discussion: Fetal obesity, associated with alterations in VLDL lipid fatty acid composition, represents an important risk factor for adult obesity and diabetes.     

Regulation of lipid flux between liver and adipose tissue during transient hepatic steatosis in carnitine-depleted rats

Rats with carnitine deficiency due to trimethylhydrazinium propionate (mildronate) administered at 80 mg/100 g body weight per day for 10 days developed liver steatosis only upon fasting. This study aimed to determine whether the transient steatosis resulted from triglyceride accumulation due to the amount of fatty acids preserved through impaired fatty acid oxidation and/or from up-regulation of lipid exchange between liver and adipose tissue. In liver, mildronate decreased the carnitine content by approximately 13-fold and, in fasted rats, lowered the palmitate oxidation rate by 50% in the perfused organ, increased 9-fold the triglyceride content, and doubled the hepatic very low density lipoprotein secretion rate. Concomitantly, triglyceridemia was 13-fold greater than in controls. Hepatic carnitine palmitoyltransferase I activity and palmitate oxidation capacities measured in vitro were increased after treatment. Gene expression of hepatic proteins involved in fatty acid oxidation, triglyceride formation, and lipid uptake were all increased and were associated with increased hepatic free fatty acid content in treated rats. In periepididymal adipose tissue, mildronate markedly increased lipoprotein lipase and hormone-sensitive lipase activities in fed and fasted rats, respectively. On refeeding, carnitine-depleted rats exhibited a rapid decrease in blood triglycerides and free fatty acids, then after approximately 2 h, a marked drop of liver triglycerides and a progressive decrease in liver free fatty acids. Data show that up-regulation of liver activities, peripheral lipolysis, and lipoprotein lipase activity were likely essential factors for excess fat deposit and release alternately occurring in liver and adipose tissue of carnitine-depleted rats during the fed/fasted transition.     

Contributions of fatty acid and sterol synthesis to triglyceride and cholesterol secretion by the perfused rat liver in genetic hyperlipemia and obesity

The relative importance of fatty acid synthesis in triglyceride secretion by perfused livers from lean (normal control) and obese Zucker rats was investigated. Livers from fed animals were perfused in a recirculating system with tritiated water and a constant infusion of oleic acid. Triglyceride secretion was 5 times greater and cholesterol secretion was 35% greater in the obese rat livers. The very-low-density lipoprotein hypersecreted by perfused livers from obese rats contained more apolipoprotein B and exhibited an increased B-48/B-100 ratio. Apo-B was also elevated in the hypertriglyceridemic plasma of obese rats in both fed and fasting states. The very-low-density lipoprotein isolated therefrom was likewise characterized by an increased B-48/B-100 ratio. Ketogenesis was depressed 40% in the obese rat livers and increased hepatic malonyl-CoA was implicated in this alteration. The de novo synthesis and secretion of newly synthesized cholesterol was moderately increased in the perfused livers from obese rats. Tritium incorporation into fatty acids was 15 times greater in the obese genotype. Most of the synthesized fatty acids remained in the liver and were recovered after perfusion in triglyceride and phospholipids. Newly synthesized fatty acids accounted for only 3 and 15% of the triglyceride secreted by the lean and obese rat livers, respectively. A large portion of the secreted triglyceride fatty acids was derived from endogenous liver lipids. When the turnover of newly synthesized fatty acids in these pools was considered, the contribution of de novo fatty acid synthesis to triglyceride secretion was estimated to be 9% in the lean and 44% in the obese rat livers. Therefore, the altered partition of free fatty acids (Fukuda, N., Azain, M. J., and Ontko, J. A. (1982) J. Biol. Chem. 257, 14066-14072) and increased fatty acid synthesis are both major determinants of the hypersecretion of triglyceride-rich lipoproteins by the liver in the genetically obese Zucker rat.     

Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat.

The corpulent JCR:LA-cp rat (cp/cp) is a useful model for study of the metabolic consequences of obesity and hyperinsulinemia. To assess the effect of hyperinsulinemia on VLDL secretion in this model, we measured rates of secretion of VLDL in perfused livers derived from cp/cp rats and their lean littermates. Livers of cp/cp rats secreted significantly greater amounts of VLDL triglyceride and apolipoprotein, compared with lean littermates. The content of apoB, apoE, and apoCs in both perfusate and plasma VLDL was greater in the cp/cp rat, as was the apolipoprotein (apo)C, apoA-I, and apoA-IV content of plasma HDL. Triglyceride content was also greater in cp/cp livers, as was hepatic lipogenesis and expression of lipogenic enzymes and sterol regulatory element binding protein-1 (SREBP-1). Hepatic mRNAs for apoE, and apoA-I were higher in livers of cp/cp rats. In contrast, the steady state levels of apoC-II, apoC-III, and apoB mRNAs were unchanged. Thus, livers of obese hyperinsulinemic cp/cp JCR:LA-cp rats secrete a greater number of VLDL particles that are enriched in triglyceride, apoE, and apoC. Greater secretion of VLDL in the cp/cp rat in part results from higher endogenous fatty acid synthesis, which in turn may occur in response to increased expression of the lipogenic enzyme regulator SREBP-1c.     

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.     

Oxidation and esterification of cis- and trans-isomers of octadecenoic and octadecadienoic acids in isolated rat liver

The metabolism of 9-octadecenoic and 9,12-octadecadienoic acids with different geometrical configurations was compared in isolated perfused rat liver. More ketone bodies were produced when the trans-isomers were infused. In contrast, only the cis-isomer augmented the triacylglycerol secretion almost entirely as very-low-density lipoprotein (VLDL). Although these responses were independent of the difference in the degree of unsaturation in both the cis- and trans-isomers, the trans-monoenic acid compared to the trans-dienic acid was incorporated more readily into perfusate and hepatic lipids. Quantitative information was obtained with radioactive tracer experiments. The hepatic uptakes of 9-[10-14C]octadecenoic acids were comparable in the cis- and trans-isomers. The trans-octadecenoic acid compared to the cis counterpart was oxidized more readily and incorporated more into liver phospholipid but less into perfusate and liver triacylglycerol. These reciprocal responses counterbalanced each other. The lower rates of triacylglycerol synthesis and secretion in the liver perfused with the trans-octadecenoic acid was confirmed using [2- 3H]glycerol as a tracer. The marked difference in the channelling of cis- and trans-fatty acids in the pathways of oxidation and esterification seems to modify the VLDL secretion in perfused rat liver. Present observations indicate a considerable difference in the fate of unsaturated fatty acids with different configurations. trans-Fatty acids are expected to be an efficient energy source in animal tissues and may not be hyperlipidemic.     

Lipid composition of liver peroxisomes isolated from untreated and clofibrate-treated mice and rats

Peroxisomes were isolated from liver tissue of control and clofibrate-treated adult male NMRI mice and Sprague-Dawley rats. Phospholipids, cholesterol, triglycerides and free fatty acids were measured in the peroxisomes. The fatty acid profiles of the phosphatidylethanolamine, the phosphatidylcholine, the triglyceride and the free fatty acid fractions were also analyzed. Phosphatidylethanolamine was the dominating phospholipid in peroxisomes from untreated animals. The fatty acid profiles of phosphatidylethanolamine, free fatty acids and triglycerides were similar for untreated mice and rats but differences between the species were observed in the pattern derived from phosphatidylcholine. Phosphatidylcholine was the most abundant phospholipid after clofibrate treatment. Clofibrate treatment caused an increase in the concentrations of phospholipids and unsaturated long-chain fatty acids and a decrease in the concentrations of triglycerides, free fatty acids, cholesterol and shorter saturated fatty acids.     

Stimulation by oleic acid of incorporation of L-[4,5-3H]leucine into very low density lipoprotein apoprotein by the isolated perfused rat liver

Livers from normal fed or fasted (24h) rats were perfused in vitro to determine whether fatty acid affects the biosynthesis of very low density lipoprotein (VLDL) apoprotein. Oleate stimulated VLDL triacylglycerol output and increased incorporation of L-[4,5-3H]leucine into VLDL apoprotein in both the fed and fasted groups. The increased incorporation of [3H]leucine was mainly into VLDL-apoprotein E. The total mass of VLDL apoprotein secreted was also stimulated by oleate proportionately. These data suggest that fatty acids may stimulate hepatic synthesis and/or secretion of the VLDL apoproteins and that apo E, may be required for the formation and secretion of triacyl-glycerol in the VLDL.