Bile diversion in rats leads to a decreased plasma concentration of linoleic acid which is not due to decreased net intestinal absorption of dietary linoleic acid

Decreased bile secretion into the intestine has been associated with low plasma concentrations of essential fatty acids (EFA) in humans. We studied the mechanism behind this relationship by determining the status and absorption of the major dietary EFA, linoleic acid (LA), in control and 1-week bile-diverted rats. The absorption of LA was quantified by a balance method and by measuring plasma concentrations of [13C]LA after its intraduodenal administration. Absolute and relative concentrations of LA in plasma were decreased in bile-diverted rats (P<0.01 and P<0.001, respectively). Fecal excretion of LA was increased at least 20-fold in bile-diverted rats (0.72+/-0.11 vs. 0.03+/-0.00 mmol/day; P<0.0001). Due to increased chow ingestion by bile-diverted rats, net intestinal absorption of LA was similar between bile-diverted and control rats (1.96+/-0.14 vs. 1.91+/-0.07 mmol/day, respectively; P>0.05). After intraduodenal administration of [13C]LA, plasma concentrations were approximately 3-4-fold lower in bile-diverted rats for at least 6 h (P<0.001). Plasma concentrations of both [12C]arachidonic acid and [13C]arachidonic acid were increased in bile-diverted rats (P<0.05). We conclude that decreased plasma concentrations of LA in 1-week bile-diverted rats are not due to decreased net intestinal absorption of LA, but may be related to increased metabolism of LA.     

Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism

Rats with long-term cholestasis have reduced ketosis during starvation. Because it is unclear whether this is also the case in short-term cholestasis, we investigated hepatic fatty acid metabolism in rats with bile duct ligation for 5 days (BDL5, n = 11) or 10 days (BDL10, n = 11) and compared the findings with those made with pair-fed control rats (CON5 and CON10, n = 11). The plasma beta-hydroxybutyrate concentration was reduced in BDL rats (0.54 +/- 0.10 vs. 0.83 +/- 0.30 mM at 5 days and 0.59 +/- 0.24 vs. 0.88 +/- 0.09 mM at 10 days in BDL and control rats, respectively). In isolated liver mitochondria, state 3 oxidation rates for various substrates were not different between BDL and control rats. Production of ketone bodies from [(14)C]palmitate was reduced by 40% in mitochondria from BDL rats at both time points, whereas production of (14)CO(2) was maintained. These findings indicated intact function of the respiratory chain, Krebs cycle, and beta-oxidation and suggested impaired ketogenesis (HMG-CoA pathway). Accordingly, the formation of acetoacetate from acetyl-CoA by disrupted mitochondria was reduced in BDL rats at 5 days (2.1 +/- 1.0 vs. 4.8 +/- 1.9 nmol/min per mg protein) and at 10 days (1.7 +/- 1.0 vs. 6.2 +/- 1.9 nmol/min per mg protein). The principal defect could be localized at the rate-limiting enzyme of the HMG-CoA pathway, HMG-CoA synthase, which revealed decreased activity, and reduced hepatic mRNA and protein levels. We conclude that short-term cholestasis in rats leads to impaired hepatic fatty acid metabolism due to impaired ketogenesis. Ketogenesis is impaired because of decreased mRNA levels of HMG-CoA synthase, leading to reduced hepatic protein levels and to decreased activity of this key enzyme of ketogenesis. - Lang, C., M. Sch?fer, D. Serra, F. G. Hegardt, L. Kr?henbühl, and S. Kr?henbühl. Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism. J. Lipid Res. 2001. 42: 22;-30.     

In vivo investigation of the placental transfer of (13)C-labeled fatty acids in humans

Placental fatty acid transfer in humans in vivo was studied using stable isotopes. Four pregnant women undergoing cesarean section received 4 h before delivery an oral dose of [(13)C]palmitic acid (PA), [(13)C]oleic acid (OA), [(13)C]linoleic acid (LA), and [(13)C]docosahexaenoic acid (DHA). Maternal blood samples were collected at -4 h (basal), -3 h, -2 h, -1 h, 0 h, and +1 h relative to time of cesarean section. At the time of birth, venous cord blood and placental tissue were collected. Fatty acid composition was determined by gas-liquid chromatography and isotopic enrichment by gas chromatography-combustion-isotope ratio mass spectrometry. (13)C-enrichment of fatty acids in the nonesterified fatty acids (NEFA) of cord plasma tended to be higher than in NEFA of placenta, with statistically significant differences for the nonesterified OA and DHA ([(13)C]PA, 0.024 +/- 0.011 vs. 0.001 +/- 0.001; [(13)C]OA, 0.042 +/- 0.008 vs. 0.005 +/- 0.003; [(13)C]LA, 0.038 +/- 0.010 vs. 0.008 +/- 0.002; [(13)C]DHA, 0.059 +/- 0.009 vs. 0.010 +/- 0.003). The ratio of tracer fatty acid concentrations of placenta to maternal plasma was significantly higher for [(13)C]DHA than for the other fatty acids ([(13)C]PA, 7.1 +/- 1%; [(13)C]OA, 3.8 +/- 0.4%; [(13)C]LA, 9.2 +/- 1.3%; [(13)C]DHA, 25.9 +/- 3.4%). These results suggest that only a part of the placental NEFA participated in fatty acid transfer, and that the placenta showed a preferential accretion of DHA relative to the other fatty acids.     

Biliary phospholipid secretion is not required for intestinal absorption and plasma status of linoleic acid in mice.

Biliary phospholipids have been hypothesized to be important for essential fatty acid homeostasis. We tested this hypothesis by investigating the intestinal absorption and the status of linoleic acid in mdr2 Pgp-deficient mice which secrete phospholipid-free bile. In mice homozygous (-/-) for disruption of the mdr2 gene and wild-type (+/+) mice, dietary linoleic acid absorption was determined by 72 h balance techniques. After enteral administration, [(13)C]-linoleic acid absorption was determined by measuring [(13)C]-linoleic acid concentrations in feces and in plasma. The status of linoleic acid was determined in plasma and in liver by calculating the molar percentage of linoleic acid and the triene:tetraene ratio. Although plasma concentration of [(13)C]-linoleic acid at 2 h after enteral administration was significantly lower in (-/-) compared to (+/+) mice (P相似文献   

Metabolic effects of intravenous LCT or MCT/LCT lipid emulsions in preterm infants

Most lipid emulsions for parenteral feeding of premature infants are based on long-chain triacylglycerols (LCTs), but inclusion of medium-chain triacylglycerols (MCTs) might provide a more readily oxidizable energy source. The influence of these emulsions on fatty acid composition and metabolism was studied in 12 premature neonates, who were randomly assigned to an LCT emulsion (control) or an emulsion with a mixture of MCT and LCT (1:1). On study day 7, all infants received [13C]linoleic (LA) and [13C]alpha-linolenic acid (ALA) tracers orally. Plasma phospholipid (PL) and triacylglycerol (TG) fatty acid composition and 13C enrichments of plasma PL fatty acids were determined on day 8. After 8 days of lipid infusion, plasma TGs in the MCT/LCT group had higher contents of C8:0 (0.50 +/- 0.60% vs. 0.10 +/- 0.12%; means +/- SD) and C10:0 (0.66 +/- 0.51% vs. 0.15 +/- 0.17%) than controls. LA content of plasma PLs was slightly lower in the MCT/LCT group (16.47 +/- 1.16% vs. 18.57 +/- 2.09%), whereas long-chain polyunsaturated derivatives (LC-PUFAs) of LA and ALA tended to be higher. The tracer distributions between precursors and products (LC-PUFAs) were not significantly different between groups. Both lipid emulsions achieve similar plasma essential fatty acid (EFA) contents and similar proportional conversion of EFAs to LC-PUFAs. The MCT/LCT emulsion seems to protect EFAs and LC-PUFAs from beta-oxidation.     

Plasma fatty acids and [13C]linoleic acid metabolism in preterm infants fed a formula with medium-chain triglycerides

Most preterm infant formulas contain medium-chain triacylglycerols (MCT), but the effects of MCT on polyunsaturated fatty acid status and metabolism are controversial. Thus, we studied the effects of MCT on linoleic acid metabolism using stable isotopes. Enterally fed preterm infants were randomized to receive for 7 days 40% of fat as MCT (n = 10) or a formula without MCT (n = 9). At study day 5, infants received orally 2 mg/kg body weight of (13)C-labeled linoleic acid. Fatty acids in plasma lipid classes and (13)C enrichment of phospholipid fatty acids were measured and tracer oxidation was monitored. Compared with the control group, the MCT group showed lower breath (13)CO(2) and higher plasma triacylglycerol contents of octanoic acid, of decanoic acid, and of total long-chain polyunsaturated fatty acids (57.1 +/- 4.4 micro mol/l vs. 37.9 +/- 4.8 micro mol/l, P < 0.01). Concentrations of several polyunsaturated fatty acids in plasma phospholipids and non esterified fatty acids were higher in the MCT group. (13)C concentrations in phospholipid n-6 fatty acids indicated no difference in the relative conversion of linoleic to arachidonic acid. We conclude that oral MCT effectively reduce polyunsaturated fatty acid and long chain polyunsaturated fatty acid oxidation in preterm infants without compromising endogenous n-6 long chain polyunsaturated fatty acid synthesis.     

A comparison of the metabolism of eighteen-carbon 13C-unsaturated fatty acids in healthy women

Altered use of different dietary fatty acids may contribute to several chronic diseases, including obesity, noninsulin-dependent diabetes mellitus, and cardiovascular disease. However, few comparative data are available to support this link, so the goal of the present study was to compare the metabolism of [(13)C]oleate, [(13)C]alpha-linolenate, [(13)C]elaidate, and [(13)C]linoleate through oxidation and incorporation into plasma lipid fractions and adipose tissue. Each tracer was given as a single oral bolus to six healthy women. Samples were collected over 8 days, and (13)C was analyzed using isotope ratio mass spectrometry. At 9 h postdose, cumulative oxidation was similar for [(13)C]elaidate, [(13)C]oleate, and [(13)C]alpha-linolenate (19 +/- 1%, 20 +/- 4%, and 19 +/- 3% dose, respectively). Significantly lower oxidation of [(13)C]linoleate (12 +/- 4% dose; P < 0.05) was accompanied by its higher incorporation into plasma phospholipids and cholesteryl esters. Abdominal adipose tissue was enriched with [(13)C]alpha-linolenate, [(13)C]elaidate, or [(13)C]linoleate within 6 h. The percentage linoleate in plasma phospholipids correlated positively with [(13)C]linoleate and [(13)C]elaidate oxidation, indicating a potential role of background diet. Conversion of [(13)C]linoleate and [(13)C]alpha-linolenate to longer chain polyunsaturates was a quantitatively minor route of utilization.     

Isomerization increases the postprandial oxidation of linoleic acid but not alpha-linolenic acid in men

Human lipid intake contains various amounts of trans fatty acids. Refined vegetable and frying oils, rich in linoleic acid and/or alpha-linolenic acid, are the main dietary sources of trans-18:2 and trans-18:3 fatty acids. The aim of the present study was to compare the oxidation of linoleic acid, alpha-linolenic acid, and their major trans isomers in human volunteers. For that purpose, TG, each containing two molecules of [1-(13)C]linoleic acid, alpha-[1-(13)C]linolenic acid, [1-(13)C]-9cis,12trans-18:2, or [1-(13)C]-9cis,12cis,15trans-18:3, were synthesized. Eight healthy young men ingested labeled TG mixed with 30 g of olive oil. Total CO(2) production and (13)CO(2) excretion were determined over 48 h. The pattern of oxidation was similar for the four fatty acids, with a peak at 8 h and a return to baseline at 24 h. Cumulative oxidation over 8 h of linoleic acid, 9cis,12trans-18:2, alpha-linolenic acid, and 9cis,12cis,15trans-18:3 were, respectively, 14.0 +/- 4.1%, 24.7 +/- 6.7%, 23.6 +/- 3.3%, and 23.4 +/- 3.7% of the oral load, showing that isomerization increases the postprandial oxidation of linoleic acid but not alpha-linolenic acid in men.     

Altered cardiac metabolic phenotype after prolonged inhibition of NO synthesis in chronically instrumented dogs

Acute inhibition of nitric oxide (NO) synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1) po) for 10 days to inhibit NO synthesis, and seven were used as controls. Cardiac free fatty acid, glucose, and lactate oxidation were measured by infusion of [(3)H]oleate, [(14)C]glucose, and [(13)C]lactate, respectively. After 10 days of L-NAME administration, despite no differences in left ventricular afterload, cardiac O(2) consumption was significantly increased by 30%, consistent with a marked enhancement in baseline oxidation of glucose (6.9 +/- 2.0 vs. 1.7 +/- 0.5 micromol.min(-1).100 g(-1), P < 0.05 vs. control) and lactate (21.6 +/- 5.6 vs. 11.8 +/- 2.6 micromol.min(-1).100 g(-1), P < 0.05 vs. control). When left ventricular afterload was increased by ANG II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the L-NAME than in the control group, whereas free fatty acid oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 micromol.kg(-1).min(-1) iv) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase activity and protein expression were higher (38 and 34%, respectively) in the L-NAME than in the control group. Also, protein expression of the constitutively active glucose transporter GLUT-1 was significantly elevated (46%) vs. control. We conclude that prolonged NO deficiency causes a profound alteration in cardiac metabolic phenotype, characterized by selective potentiation of carbohydrate oxidation, that cannot be reversed by a short-term infusion of exogenous NO. This phenomenon may constitute an adaptive mechanism to counterbalance cardiac mechanical inefficiency.     

Administration of phosphatidylcholine-cholesterol liposomes partially reconstitutes fat absorption in chronically bile-diverted rats

BACKGROUND AND AIMS: Intestinal bile deficiency in cholestatic patients leads to fat malabsorption. We addressed the potency of model bile, bile salts and phosphatidylcholine (PC)-cholesterol (CH) liposomes to reconstitute fat absorption in permanently bile-diverted (BD) rats. METHODS: The plasma appearance of 13C-labeled palmitic acid (13C-16:0) and linoleic acid (13C-18:2) was determined after their enteral administration to BD or to control rats with an intact enterohepatic circulation (EHC) (13C-16:0 and 13C-18:2 dissolved in 25% olive oil-75% medium chain triacylglycerol oil mixture). BD rats were intraduodenally infused with buffer, model bile [consisting of 60 mM taurocholate (TC), 8 mM PC and 1 mM CH], buffer with TC, buffer with PC and CH liposomes, or buffer with lyso-PC and CH. RESULTS: Plasma concentrations of 13C-16:0 and 13C-18:2 were consistently three- to eightfold higher in control rats than those in buffer-infused BD rats (P < 0.01). ID administration of either model bile or TC to BD rats restored plasma appearance of 13C-fatty acids at least to concentrations observed in control rats. Administration of PC + CH liposomes to BD rats partially reconstituted the plasma appearance of 13C-16:0, but did not affect that of 13C-18:2. Compared with control rats, the area under the curve (AUC) of plasma 13C-16:0 concentrations was 13.0 +/- 6.9% in buffer-infused rats and 40.9 +/- 3.1% in liposome-infused rats (P < 0.005). CONCLUSIONS: Enteral administration of PC + CH liposomes to BD rats partially corrects the absorption of palmitic acid. Present data suggest that administration of PC + CH liposomes could enhance fat absorption in clinical conditions of cholestasis in which bile salt supplemention is contraindicated.     

Impaired synthesis of DHA in patients with X-linked retinitis pigmentosa

Many patients with X-linked retinitis pigmentosa (XLRP) have lower than normal blood levels of the long-chain polyunsaturated omega3 fatty acid docosahexaenoic acid (DHA; 22:6omega3). This clinical trial was designed to test whether down-regulation of DHA biosynthesis might be responsible for these reduced DHA levels. DHA biosynthesis was assessed in five severely affected patients with XLRP and in five age-matched controls by quantifying conversion of [U-(13)C]alpha-linolenic acid (alpha-LNA) to [(13)C]DHA. Following oral administration of [U-(13)C]alpha-LNA, blood samples were collected at designated intervals for 21 days and isotopic enrichment of all omega3 fatty acids was determined by gas chromatography/mass spectroscopy. Activity of each metabolic step in the conversion of alpha-LNA to DHA was determined by comparison of the ratios of the integrated concentration of (13)C-product to (13)C-precursor in plasma total lipid fractions. The ratio of [(13)C]DHA to [(13)C]18:3omega3 (the entire pathway) and that of [(13)C]20:5omega3 to [(13)C]20:4omega3 (Delta(5)-desaturase) were significantly lower in patients versus controls (P = 0.03 and 0.05, respectively). The estimated biosynthetic rates of [(13)C]20:5omega3, [(13)C]22:5omega3, [(13)C]24:5omega3, [(13)C]24:6omega3, and [(13)C]22:6omega3 were significantly lower in XLRP patients (42%, 43%, 31%, 18%, and 32% of control values, respectively; P < 0.04), supporting down-regulation of Delta(5)-desaturase in XLRP. The disappearance of (13)C-labeled fatty acids from plasma was not greater in XLRP patients compared with controls, suggesting that XLRP was not associated with increased rates of fatty acid oxidation or other routes of catabolism.Thus, despite individual variation among both patients and controls, the data are consistent with a lower rate of Delta(5)-desaturation, suggesting that decreased biosynthesis of DHA may contribute to lower blood levels of DHA in patients with XLRP.     

Specific linoleate deficiency in the rat does not prevent substantial carbon recycling from [(14)C]linoleate into sterols

Compared with classic essential fatty acid deficiency or the feeding of a fat-free diet, little is known about specific linoleate deficiency in the rat. Carbon recycling into de novo lipogenesis has been reported to be an obligatory feature of linoleate metabolism in the liver, even in extreme linoleate deficiency (LA-D). The present study had two objectives: 1) to report a brief summary of the tissue n-6 polyunsaturated fatty acid (PUFA) profiles in specific LA-D, and 2) to quantify whole body carbon recycling from [(14)C]linoleate in specific LA-D. Rats consumed a linoleate-deficient diet for 12 weeks and then received a bolus of [1-(14)C]linoleate by gavage. In linoleate-deficient rats, the triene/tetraene ratio in several organs increased by 18- to 100-fold. The amount of (14)C appearing in organ sterols (dpm/g) of linoleate-deficient rats was 2- to 10-fold higher than in the controls and equaled 16.3% of the [(14)C]linoleate dose given, compared with 7.4% in the controls. We conclude that a similar amount (about 10%) of the carbon skeleton of linoleate is normally recycled into lipids synthesized de novo, as remains in the whole body pool of n-6 polyunsaturates.     

Hydrogenation alternatives: effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans.

The objective of this study was to compare the effects of linoleic acid (cis,cis-C18:2(n-6)) and its hydrogenation products elaidic (trans-C18:1(n-9)) and stearic acid (C18:0) on serum lipoprotein levels in humans. Twenty-six men and 30 women, all normolipemic and apparently healthy, completed the trial. Three experimental diets were supplied to every subject for 3 weeks each, in random order (multiple cross-over). The Linoleate-diet provided 12.0% of total energy intake as linoleic acid, 2.8% as stearic acid, and 0.1% as trans fatty acids. The Stearate-diet supplied 3.9 energy % as linoleic acid, 11.8% stearic acid, and 0.3% trans fatty acids. The Trans-diet provided 3.8 energy % as linoleic acid, 3.0% stearic acid, and 7.7% as monounsaturated trans fatty acids, largely elaidic acid (trans-C18:1(n-9)). Other nutrients were constant. Fasting blood was sampled at the end of each dietary period. Mean (+/- SD) serum LDL cholesterol was 109 +/- 24 mg/dl (2.83 +/- 0.63 mmol/l) on the Linoleate-diet. It rose to 116 +/- 27 mg/dl (3.00 +/- 0.71 mmol/l) on the Stearate-diet (change, 7 mg/dl or 0.17 mmol/l, P = 0.0008) and to 119 +/- 25 mg/dl (3.07 +/- 0.65 mmol/l) on the Trans-diet (change, 9 mg/dl or 0.24 mmol/l, P less than 0.0001). High density lipoprotein (HDL) cholesterol decreased by 2 mg/dl (0.06 mmol/l, P less than 0.0001) on the Stearate-diet and by 4 mg/dl (0.10 mmol/l, P less than 0.0001) on the Trans-diet, both relative to linoleic acid. Our findings show that 7.7% of energy (mean, 24 g/day) of trans fatty acids in the diet significantly lowered HDL cholesterol and raised LDL cholesterol relative to linoleic acid. Combination with earlier results (Mensink, R. P., and M. B. Katan. 1990. N. Engl. J. Med. 323: 439-445) suggests a linear dose-response relation. Replacement of linoleic acid by stearic acid also caused somewhat lower HDL cholesterol and higher LDL cholesterol levels. Hydrogenation of linoleic acid to either stearic or trans fatty acids produces fatty acids that may increase LDL and decrease HDL cholesterol relative to linoleic acid itself.     

Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status

In addition to decreased insulin sensitivity, diabetes is a pathological condition associated with increased inflammation. The ω-3 fatty acids have been proposed as anti-inflammatory agents. Thus, the major goal of this study was to analyze the effects of fatty acid supplementation on both insulin sensitivity and inflammatory status in an animal model of type 2 diabetes. Diabetic rats (Goto-Kakizaki model) were treated with eicosapentaenoic acid (EPA) or linoleic acid at 0.5 g/kg body weigh (bw) dose. In vivo incorporation of (14)C-triolein into adipose tissue was improved by the ω-3 administration. In vitro incubations of adipose tissue slices from EPA-treated rats showed an increase in (14)C-palmitate incorporation into the lipid fraction. These observations were linked with a decreased rate of fatty acid oxidation. EPA treatment resulted in a decreased fatty acid oxidation in incubated strips from extensor digitorum longus (EDL) muscles. The changes in lipid utilization were associated with a decrease in insulin plasma concentration, suggesting an improvement in insulin sensitivity. These changes in lipid metabolism were associated with an activation of AMP-activated protein kinase (AMPK) in white adipose tissue. In addition, EPA treatment resulted in a decreased content of peroxisome proliferator-activated receptor-α (PPARα) and PPARδ and in increased GLUT4 expression in skeletal muscle. Moreover, EPA increased 2-deoxy-D-[(14)C]glucose (2-DOG) uptake in C2C12 myotubes, suggesting an improvement in glucose metabolism. Concerning the inflammatory status, EPA treatment resulted in a decreased gene expression for both tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) both in skeletal muscle and adipose tissue. The data suggest that EPA treatment to diabetic rats clearly improves lipid metabolism although the evidences on insulin sensitization are less clear.     

Effect of gender on lipid kinetics during endurance exercise of moderate intensity in untrained subjects

We evaluated lipid metabolism during 90 min of moderate-intensity (50% VO(2) peak) cycle ergometer exercise in five men and five women who were matched on adiposity (24 +/- 2 and 25 +/- 1% body fat, respectively) and aerobic fitness (VO(2) peak: 49 +/- 2 and 47 +/- 1 ml x kg fat-free mass(-1) x min(-1), respectively). Substrate oxidation and lipid kinetics were measured by using indirect calorimetry and [(13)C]palmitate and [(2)H(5)]glycerol tracer infusion. The total increase in glycerol and free fatty acid (FFA) rate of appearance (R(a)) in plasma during exercise (area under the curve above baseline) was approximately 65% greater in women than in men (glycerol R(a): 317 +/- 40 and 195 +/- 33 micromol/kg, respectively; FFA R(a): 652 +/- 46 and 453 +/- 70 micromol/kg, respectively; both P < 0.05). Total fatty acid oxidation was similar in men and women, but the relative contribution of plasma FFA to total fatty acid oxidation was higher in women (76 +/- 5%) than in men (46 +/- 5%; P < 0.05). We conclude that lipolysis of adipose tissue triglycerides during moderate-intensity exercise is greater in women than in men, who are matched on adiposity and fitness. The increase in plasma fatty acid availability leads to a greater rate of plasma FFA tissue uptake and oxidation in women than in men. However, total fat oxidation is the same in both groups because of a reciprocal decrease in the oxidation rate of fatty acids derived from nonplasma sources, presumably intramuscular and possibly plasma triglycerides, in women.     

Fat absorption in essential fatty acid deficiency: a model experimental approach to studies of the mechanism of fat malabsorption of unknown etiology

Male rats were made deficient in essential fatty acids by feeding them a fat-free diet supplemented with 4% tripalmitin for 8-12 wk from the time of weaning. After feeding 0.5 ml of [(14)C]triolein or [(3)H]oleic acid, 72-hr stool recoveries of radioactivity were significantly greater in deficient rats than in chow-fed controls. Essential fatty acid deficiency did not reduce the absorptive capacities for triolein or for a medium-chain fat, trioctanoin, measured after 3 and 2 hr of maximal-rate duodenal infusion. In everted jejunal slices from essential fatty acid-deficient rats, uptake of micellar [(14)C]oleic acid at 0-1 degrees C was similar to that of controls, but the rate of incorporation of fatty acid into triglyceride after rewarming to 37 degrees C was significantly reduced. The specific activities of the microsomal esterifying enzymes, acyl CoA:monoglyceride acyltransferase and fatty acid CoA ligase in jejunal mucosa were 30% lower in essential fatty acid-deficient rats. However, the total microsomal enzyme activity adjusted to constant weight did not differ significantly in deficient rats compared with controls. After intraduodenal perfusion of triolein, accumulation of lipid in the intestinal wall was increased in the deficient rats. Because over 90% of the absorbed mucosal lipid was present as triglyceride, essential fatty acid deficiency appears to affect the synthesis or release of chylomicron lipid from the intestine. Analysis of regions of intestine showed that this delay in transport was most marked in the midportion of the small intestine.     

The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts

Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague-Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs-Henseleit solution containing 11 mmol/L glucose, 100 muU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output x heart rate (in (mL/min).(beats/min).10-2), was deteriorated in diabetic (73 +/- 4) and TMZ-treated diabetic (61 +/- 7) groups compared with control (119 +/- 3) and TMZ-treated controls (131 +/- 6). TMZ treatment increased coronary flow in TMZ-treated control (23 +/- 1 mL/min) hearts compared with untreated controls (18 +/- 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 mumol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.     

The effects of streptozotocin diabetes and of dietary protein content on the composition and metabolism of testicular lipids

The effect of streptozotocin-induced diabetes on the fatty acid composition and metabolism in testes of rats on diets varying in protein content has been investigated. The protein content of the diet (40, 20, 5%) had little or no effect on essential fatty acid metabolism during the 2 weeks following injection of streptozotocin, but the 5% diet resulted in a high rate of mortality for diabetic rats. Increased amounts of octadeca-9,12-dienoic (linoleic or 18:2) acid and of eicosa-8,11,14-trienoic (dihomo-gamma-linolenic or 20:3) acid and decreased amounts of eicosa-5,8,11,14-tetraenoic (arachidonic or 20:4) acid were observed in testes of some but not all diabetic compared to pair-fed control rats 2 weeks after injection of streptozotocin. Incorporation of 14C from [14C]18:2 into testicular lipids of these rats was determined 26 hr after intratesticular injection. In some rats there was a greater amount of 14C in eicosa-11,14-dienoic acid (dihomolinoleic acid or 20:2) and 20:3 and less 14C in 20:4 of testes of diabetic than in those of control rats. The suggested impairment in conversion of 18:2 to 20:4 was studied further by using [14C]20:3 as the substrate for intratesticular injection. Four hours after administration of the [14C]polyene there was more 14C in 20:3 and less 14C in 20:4 and in docosa-7,10,13,16-tetraenoic (adrenic or 22:4) acid in testes of diabetic than in those of control rats. The results indicate that in diabetic rats at least one enzyme responsible for the decreased conversion of 18:2 to 20:4 is the delta 5-desaturase.     

Role of very low density lipoproteins in the energy metabolism of the rat

The role of very low density lipoproteins (VLDL) in the energy metabolism of conscious, 24-hr fasted rats was studied. VLDL labeled with [2-3H]glycerol and [1-14C]palmitate were infused into the rats, along with [1-13C]palmitate bound to albumin and d-8-glycerol, and various metabolic factors were assessed. The rates of appearance in plasma of fatty acids in VLDL and albumin-bound free fatty acids (FFA) were about equal, on a molar basis, and only a small fraction of the FFA flux was derived from VLDL. The rate of direct oxidation of the fatty acids from VLDL was 4.4 +/- 0.9 mumol of FA/kg X min, as compared with the value of 4.0 +/- 0.42 mumol of FA/kg X min for plasma FFA. Four percent of the plasma glycerol flux was derived from VLDL. Thus, the direct oxidation of fatty acids in VLDL played an important role in the energy metabolism of the rats, accounting for a percentage of the total CO2 production that was equal to the amount that arose from the oxidation of plasma FFA. The oxidation of VLDL-fatty acids did not involve prior entry of the fatty acids into the plasma FFA pool to any significant extent.