Trypanosoma cruzi: fatty acid metabolism in vitro.
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Animals↗
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Fatty acid metabolism and cell proliferation. III. Effect of prostaglandin biosynthesis either from exogenous fatty acid or endogenous fatty acid release with hydralazine.
Primary cultures of smooth muscle cells were established from the medial layer of guinea pig aorta. Cells were seeded at from 40 to 80 cells per cm2 and cloned for 8 days. Media were analyzed for PGI2 (6-keto-PGF1 alpha) using radioimmunoassay. Prostanoids were synthesized when cells were grown in media alone. Arachidonic acid stimulated prostanoid synthesis and promoted cell proliferation. Indomethacin blocked prostanoid synthesis and abolished the stimulatory effect of arachidonic acid on cell proliferation. Hydralazine stimulated fatty acid release and prostanoid synthesis in confluent cells. Hydralazine also stimulated prostanoid synthesis and promoted proliferation in growing cells. Indomethacin blocked prostanoid synthesis and abolished the stimulatory effect of hydralazine on cell proliferation.
6-Ketoprostaglandin F1 alpha↗
Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus.
OBJECTIVES: The purpose of this study was to determine if myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO) are increased in diabetic patients. BACKGROUND: Experimental models of diabetes mellitus demonstrate that MFAU and MFAO are increased, and that this dependence on myocardial fatty acid metabolism may be detrimental to cardiac function. Whether similar metabolic changes occur in humans with diabetes mellitus is unclear. METHODS: Eleven healthy non-diabetic control patients (5 women, ages 25 +/- 5 years) and 11 otherwise healthy patients with type 1 diabetes mellitus (T1DM) (8 women, ages 36 +/- 10 years, HbA1c 8.4 +/- 1.9%) underwent positron emission tomography for the determination of myocardial blood flow (MBF); myocardial oxygen consumption (MVO2); myocardial glucose utilization (MGU); and MFAU, MFAO, and %MFAO. RESULTS: Plasma lactate, insulin, and MBF levels were similar between the two groups. However, plasma glucose (5.71 +/- 0.98 mumol/ml vs. 5.28 +/- 0.65 mumol/ml, p = 0.04), free fatty acid levels (0.60 +/- 0.24 mumol/ml vs. 0.19 +/- 0.07 mumol/ml, p < 0.0001), and MVO2 (6.64 +/- 2.21 vs. 4.51 +/- 1.39 mumol/g/min, p = 0.007) levels were higher in the T1DM subjects. Furthermore, compared with control patients, T1DM subjects exhibited higher MFAU (213 +/- 135 nmol/g/min vs. 57 +/- 28 nmol/g/min, p = 0.0004), MFAO (206 +/- 131 nmol/g/min s. 50 +/- 26 nmol/g/min, p = 0.0002), and %MFAO (94 +/- 6% vs. 81 +/- 19%, respectively, p = 0.04). In contrast, MGU was lower in T1DM subjects than in controls (207 +/- 108 nmol/g/min vs. 403 +/- 191 nmol/g/min, p = 0.0008). CONCLUSIONS: Humans with diabetes mellitus exhibit increased MFAU and MFAO and reduced MGU consistent with observations obtained in experimental models of diabetes.
Adult↗
Effects of 5-iodotubercidin on hepatic fatty acid metabolism mediated by the inhibition of acetyl-CoA carboxylase.
Diverse mechanisms of action have been proposed for 5-iodotubercidin, although it is widely used as an adenosine kinase inhibitor that consequently interferes with the metabolism of adenosine and adenine nucleotides. Incubation of rat hepatocytes with iodotubercidin produced important effects on lipid metabolism. (i) Both acetyl-CoA carboxylase and fatty acid synthesis de novo were inhibited in parallel by iodotubercidin, with no change in the activity of fatty acid synthase. The inhibition of both activities showed a comparable dependence on iodotubercidin concentration and was accompanied by a similar decrease (about 60%) in the intracellular malonyl-CoA concentration. (ii) Iodotubercidin stimulated palmitate oxidation, although octanoate oxidation was unaffected. However, this effect can be attributed to the decrease of malonyl-CoA concentration and the concomitant relief of the inhibition of carnitine palmitoyltransferase I, because the activity of this enzyme was found unaltered when determined in cells permeabilized with digitonin. (iii) Iodotubercidin also inhibited cholesterol synthesis de novo. Results, thus, indicate that iodotubercidin increases fatty acid oxidation activity of the liver at the expense of lipogenesis, and we suggest that these effects on fatty acid metabolism are mediated by the inhibition of acetyl-CoA carboxylase, probably due to a more than twice increase in the AMP/ATP ratio and the concomitant stimulation of the AMP-activated protein kinase.
Acetyl-CoA Carboxylase↗
Evaluation of carbon-11-labelled phenoxy bridged fatty acids for studying myocardial fatty acid metabolism with PET.
A phenylene moiety in the chain of fatty acids was expected to impair metabolic degradation. Three phenoxy-containing [11C]carboxyl-labelled fatty acids were synthesized and evaluated in mice and an in vivo tissue distribution study. Of these three, 1[11C]-3-(p-dodecyloxyphenyl)propionic acid (C12C3) showed the most favourable uptake in the myocardium: 1.2% of the injected dose at 30 min p.i., vs. 0.6% for [11C]palmitate. The metabolic stability of C12C3 and [11C]palmitate was assessed by determining the amount of exhaled [11C]CO2 during a 30-min interval after injection. It was found that the phenoxy moiety in the gamma-position did not prevent the metabolic degradation of C12C3: After 30 min 20.7% of the injected dose was exhaled as [11C]CO2 vs. 12.7% for [11C]palmitate.
Animals↗
[Successive myocardial fatty acid metabolic imaging in patients with dilated cardiomyopathy: usefulness as a prognostic indicator].
To evaluate the prognostic value of fatty acid metabolic imaging in patients with idiopathic dilated cardiomyopathy (DCM), we performed myocardial imaging with 123I-BMIPP (BMIPP). We studied 23 patients with DCM who were admitted because of congestive heart failure (CHF) and after discharge the stable condition persisted for more than one year. BMIPP imaging was obtained when CHF recovered (first study) and the second study was performed one year after the first study. From BMIPP imaging we calculated % Uptake (percentage of cardiac uptake of isotope to total injected dose) and Defect Score (degree and extent of regional abnormality in BMIPP uptake, DS). In the first study, we performed myocardial imaging with 201T1 to calculate Uptake Ratio of BMIPP (% Uptake of BMIPP divided by % Uptake of 201T1, UR). During the follow up period of 18.2 +/- 9.5 months (4.5-39.6 months) after the second study, cardiac event developed in 8 patients (cardiac death; 4, deterioration of CHF; 4). On univariate analysis, the following indices differed significantly between the event and event-free groups; left ventricular end-systolic dimension, graded DS, UR and % Uptake of 201T1 at the first study, % Uptake of BMIPP and DS at the second study, difference of % Uptake of BMIPP and DS between the first and second study, and newly designed index from graded DS of the first study and its change in the second study (Defect Index, DI). Cox proportional hazard analysis showed that DI (p = 0.0026) and age (p = 0.0262) were independent predictors of cardiac events. In patients with DI > or = 3, the relative risk of cardiac event was 25.0 times greater than that in patients with DI < or = 2. These data suggested that the extent and degree of regional abnormality of BMIPP uptake (DS) and its changes with time were useful for evaluating the prognosis in patients with DCM even though a clinically stable condition is persisting.
Adult↗
Impact on fatty acid metabolism and differential localization of FATP1 and FAT/CD36 proteins delivered in cultured human muscle cells.
We compared the intracellular distribution and regulatory role of fatty acid transporter protein (FATP1) and fatty acid translocase (FAT/CD36) on muscle cell fatty acid metabolism. With the use of adenoviruses, FATP1 and FAT genes were delivered to primary cultured human muscle cells. FATP1 and FAT moderately enhanced palmitate and oleate transport evenly at concentrations of 0.05, 0.5, and 1 mM. Long-term (16 h) consumption of palmitate and oleate from the media, and particularly incorporation into triacylglyceride (TAG), was stimulated equivalently by FATP1 and FAT at all fatty acid concentrations tested. In contrast, long-term CO(2) production was reduced by FATP1 and FAT at all doses of palmitate and at the lower concentrations of oleate. Neither FATP1 nor FAT markedly altered the production of acid-soluble metabolic intermediates from palmitate or oleate. The intracellular localization of fusion constructs of FATP1 and FAT with enhanced green fluorescent protein (EGFP) was examined. Independently of fatty acid treatment, FATPGFP was observed throughout the cytosol in a reticular pattern and concentrated in the perinuclear region, partly overlapping with the Golgi marker GM-130. FATGFP was found in the extracellular membrane and in cytosolic vesicles not coincident with GM-130. Neither FATP1 nor FAT proteins colocalized with lipid droplets in oleate-treated cells. We conclude that whereas FAT is localized on the extracellular membrane, FATP1 is active in the cytosol and imports fatty acids into myotubes. Overall, both FATP1 and FAT stimulated transport and consumption of palmitate and oleate, which they channeled away from complete oxidation and toward TAG synthesis.
Biological Transport, Active↗
Use of [123I]-BMIPP myocardial scintigraphy for the clinical evaluation of a fatty-acid metabolism disorder of the right ventricle in chronic respiratory and pulmonary vascular disease.
The objective of this study was to evaluate whether or not right ventricle (RV) uptake of iodine-123-labelled-beta-methyliodophenylpentadecanoic acid ([123I]-BMIPP) correlated with the degree of right ventricular pressure overload (RVPO). Myocardial scintigraphy of [123I]-BMIPP and thallium-201 (201Tl) was performed on 46 patients with RVPO. We determined the right ventricle (RV)/left ventricle (LV) ratio = (radioactivities of RV)/(radioactivities of LV), and the RV metabolic index (RVMI) = (RV/LV ratio of [123I]-BMIPP)/(RV/LV ratio of 201Tl). We also evaluated the correlation between RVMI and mean pulmonary arterial pressure (mPAP), and between RVMI and total pulmonary resistance (TPR). Significant correlations were found between the RV/LV ratio of [123I]-BMIPP and mPAP and between the RV/LV ratio of [123I]-BMIPP and TPR. In addition, a significant negative correlation was observed between RVMI and mPAP and between RVMI and TPR. RVMI declined as RVPO increased, suggesting the presence of a fatty-acid metabolism disorder of the RV. Moreover, [123I]-BMIPP myocardial scintigraphy could be useful for evaluating a disorder of the fatty-acid metabolism of the RV with RVPO.
Chronic Disease↗
Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism.
The human insulin resistance syndromes---type 2 diabetes, obesity, combined hyperlipidemia, and essential hypertension---are genetically complex disorders whose molecular basis is largely unknown. The spontaneously hypertensive rate (SHR) is a model of these human syndromes. In the SHR/NCrlBR strain, a chromosomal deletion event that occurred at the Cd36 locus during the evolution of this SHR strain has been proposed as a cause of defective insulin action and fatty acid metabolism. In this study, three copies of the Cd36 gene, one transcribed copy and two pseudogenes, were identified in normal rat strains, but only a single gene in SHR/NCrlBR. Analysis of SHR genomic sequence localized the chromosomal deletion event between intron 4 of the normally transcribed copy of the gene and intron 4 of the second pseudogene. The deletion led to the creation of a single chimeric Cd36 gene in SHR/NCrlBR. The boundaries of the recombination/deletion junction identified within intron 4 were surrounded by long interspersed nuclear elements (LINEs) and DNA topoisomerase I recognition sequences. An 8-bp deletion at the intron 14/exon 15 boundary of the second pseudogene abolishes the putative splice acceptor site and is the cause of an aberrant 3' UTR previously observed in SHR/NCrlBR. We conclude that in SHR/NCrlBR, the complex trait of insulin resistance and defective fatty acid metabolism is caused by Cd36 deficiency, resulting from a chromosomal deletion caused by unequal recombination. This demonstrates that chromosomal deletions caused by unequal recombination can be a cause of quantitative or complex mammalian phenotypes.
Animals↗
Reversible, highly localized alterations in fatty acid metabolism in the chronically ischemic canine myocardium.
Acute myocardial ischemia is accompanied by a marked decrease in the oxidation of fatty acids. Whether similar changes occur during chronic ischemia was studied in 13 beagles. In 10 dogs, an ameroid constrictor was implanted about the left circumflex artery; 3 others served as sham-operated controls. Mitochondrial and peroxisomal fatty acid oxidation of (1-14C)oleate were measured and compared in affected (posterobasal left ventricular endocardial [posterior LV endo]) and unaffected (anteroapical LV epicardial [anterior LV epi]) tissues of control and experimental dogs. Five experimental and 3 control dogs were killed after 3 weeks. The posterior LV endo sections of experimental dogs at 3 weeks showed increased fatty acid oxidation due to peroxisomal (KCN-insensitive) beta oxidation (p less than 0.01). The anterior LV epi sections showed no difference in fatty acid oxidation between sham-operated and experimental dogs. Five dogs were studied after 3 months; fatty acid oxidation of the posterior LV endo section was normal. Thus, under a slowly evolving state of myocardial ischemia, highly localized and reversible adaptive changes in fatty acid oxidation occur that enable the affected tissue to cope with a fatty acid load. When collateralization is accomplished, fatty acid metabolism reverts to normal.
Acyl Coenzyme A↗
[Effect of mazindol on free fatty acid metabolism in the brain of rats].
The effects of mazindol which is known as a anorexigenic agent on the free fatty acid metabolism in the brain were studied. One-half mg of mazindol was orally administered to rats weighing 500 g for 5 days. Body weight was reduced by 10%, compared to the control. Serum levels of free fatty acid, triglyceride, total cholesterol and phospholipid were decreased. The effect of mazindol on the incorporation of [1-14C] palmitic acid into various lipids in the brain were studied. When mazindol (5 mg) was administered one hr before injection of [1-14C] palmitic acid to the internal carotid artery of rats ad libitum, incorporation of [1-14C] palmitic acid into free fatty acids in the cerebrum and diencephalon was lower than that of the control, but incorporation into phospholipid and triglyceride were higher than that of the control. When mazindol was injected into fasting rats, incorporation into free fatty acid in cerebrum and diencephalon was increased compared with the control, and the incorporations into phospholipid and triglyceride were decreased.
Animals↗
Possible relevance of abnormal fatty acid metabolism in undernutrition: the relationship between oleic acid and growth.
Energy, protein, essential fatty acids, vitamins and minerals are all necessary for normal growth and development of children. In undernutrition, there is evidence for abnormal fatty acid metabolism. High levels of oleic acid and low levels of docosahexaenoic acid in plasma phosphatidylcholine have been associated with weight-for-age Z-score shifts to the left (increased prevalence of underweight) and vice versa (reduced prevalence of underweight). An alternative hypothesis is proposed, which describes a possible physiological mechanism whereby omega3 fatty acids contribute to growth. High blood oleic acid levels under conditions of undernutrition are proposed to be an adaptation to conserve glucose in the form of glycogen. Replacement with docosahexaenoic acid under conditions of adequate nutrition enhances membrane functioning so that glucose and energy become available for muscle formation.
Child↗
Lifestyle intervention and fatty acid metabolism in glucose-intolerant subjects.
OBJECTIVE: Free fatty acid (FFA) oxidation is reduced in subjects with type 2 diabetes mellitus and impaired glucose tolerance (IGT). Weight reduction does not improve these impairments. Because exercise training is known to increase fatty acid (FA) oxidation, we investigated whether a combined diet and physical activity intervention program can improve FA oxidation in subjects with IGT. RESEARCH METHODS AND PROCEDURES: Sixteen subjects with IGT were studied before and after 1 year of a lifestyle intervention program [nine intervention (INT) subjects, seven controls (CON)]. INT subjects received regular (i.e., every 3 months) dietary advice and were stimulated to increase their level of physical activity. Glucose tolerance, anthropometric characteristics, and substrate use at rest and during exercise were evaluated before and after 1 year. Substrate oxidation was measured at rest and during moderate intensity exercise using indirect calorimetry in combination with stable isotope infusion ([U-(13)C]palmitate and [6,6-(2)H(2)-]glucose). RESULTS: After 1 year, no differences were seen in substrate use at rest. During exercise, total fat and plasma FFA oxidation were slightly increased in the INT group and decreased in the CON group, with the change being significantly different (change after 1 year: INT, +2.0 +/- 1.4 and +1.9 +/- 0.9 micromol/kg per minute; CON, -3.5 +/- 1.6 and -1.8 +/- 0.5 micromol/kg per minute for total and plasma FFA, respectively; p < 0.05). DISCUSSION: A combined diet and physical activity intervention program can prevent further deterioration of impaired FA oxidation during exercise in subjects with IGT.
Diabetes Mellitus, Type 2↗
Effects of exercise training on myocardial fatty acid metabolism in rats with depressed cardiac function induced by transient ischemia.
The effects of exercise training on metabolic and functional recovery after myocardial transient ischemia were investigated in a rat model. Male Wistar Kyoto rats were subjected either to a 30-min left coronary artery occlusion followed by reperfusion or to a sham operation. At 4 weeks after operation, the rats were randomly assigned either to sedentary conditions or to exercise training for 6 weeks. In the ischemic rats, pinhole SPECT (single photon emission computed tomography) imaging with thallium-201 (201Tl) and 123I-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) showed a reduction of both myocardial perfusion and fatty acid metabolism in the risk zone of the left ventricle (LV). The LV was dilated and the ejection fraction was decreased after ischemic injury. The severity score showed a significant decrease on both 201Tl and BMIPP (201Tl, from 19.9+/-2.7 to 17.0+/-2.2, p<0.05; BMIPP, from 21.5+/-2.4 to 18.6+/-1.9, p<0.05) after exercise training in the ischemic trained rats, but did not change significantly in their sedentary counterparts. Plasma levels of free fatty acids normalized in the ischemic trained rats, but elevated in the ischemic sedentary rats (0.53+/-0.05 vs 0.73+/-0.06 mmol/L, p<0.05). Furthermore, the trained rats had a significant increase in LV stroke volume (0.25+/-0.02 vs 0.21+/-0.01 ml/beat, p<0.05) and adaptive cardiac hypertrophy. These findings demonstrate that adaptive improvements in myocardial perfusion, fatty-acid metabolism and LV function were induced by exercise training after transient ischemia.
Animals↗
Regulation of fatty-acid metabolism by pancreatic hormones in cultured human hepatocytes.
The effects of pancreatic hormones and cyclic AMP on long-chain fatty-acid metabolism were investigated in human hepatocytes isolated from 12 liver biopsy specimens and cultured for 4 days in an insulin-free medium. Glucagon (10(-6) mol/L) increased endogenous ketone body production by 150%. This resulted from alterations in the partition of long-chain fatty acids from esterification toward oxidation. Glucagon or cyclic AMP enhanced (14C) oleate oxidation (basal = 45.8% +/- 5.0%; glucagon = 66.8% +/- 5.3%; cyclic AMP = 67.6% +/- 5.0% of metabolized oleate) at the expense of oleate esterification. Insulin (10(-7) mol/L) antagonized the glucagon-induced oleate oxidation. After 24 hr in basal culture conditions, the rate of lipogenesis decreased to the same low rate as in glucagon-treated cells. The presence of insulin did not restore a high rate of lipogenesis. These results are the first direct evidence of a control of ketone body production by glucagon in the human liver.
Adult↗
Studies on plasma free-fatty-acid metabolism and triglyceride synthesis of brown adipose tissue in vivo during cold-induced thermogenesis of the newborn rabbit.
Parameters of plasma free fatty acid metabolism (pool size, half time, disappearance rate, turnover time and absolute turnover rate), the influx of plasma free fatty acids into the glycerides of brown adipose tissue and the pathway of triglyceride synthesis in brown adipose tissue (glycerol-1-phosphate versus monoglyceride pathway) were examined after intravenous injection of [1-14C]palmitate in newborn rabbits. In the thermoneutral environment of 35 degrees C the turnover rate of plasma free fatty acids was 10.20 mumol/min per 100 g body weight and its flux into the glycerides of brown adipose tissue 0.367 mumol/min per 100 g body weight. Cold exposure at an ambient temperature of 20 degrees C caused a decrease to 5.84 mumol/min and 0.207 mumol/min per 100 g body weight, respectively. Both under basal conditions at an ambient temperature of 35 degrees C and under cold-induced thermogenesis at an ambient temperature of 20 degrees C triglyceride synthesis in brown adipose tissue ran through the glycerol 1-phosphate pathway.
Adipose Tissue, Brown↗
Effect of randomly interesterified triacylglycerols containing medium- and long-chain fatty acids on energy expenditure and hepatic fatty acid metabolism in rats.
In our previous studies, medium- and long-chain triacylglycerols (MLCT), randomly interesterified triacylglycerols containing medium-chain and long-chain fatty acids in the same glycerol molecule, significantly reduced body fat accumulation in humans and rats. To clarify mechanism(s) for this effect of MLCT, we measured energy expenditure and hepatic fatty acid metabolism in rats by comparison with long-chain triacylglycerols (LCT) or medium-chain triacylglycerols (MCT). MLCT, compared with LCT, showed significantly lower body fat accumulation, higher 24-h energy expenditure and acyl-CoA dehydrogenase activity measured using octanoyl-CoA as a substrate, and similar lipogenic activity. MCT, compared with LCT, showed significantly higher energy expenditure, but fat accumulation was comparable. Additionally, MCT exhibited significantly higher lipogenic activity than the other oils. These data suggest that enhancement of energy expenditure and medium-chain fatty acids (MCFA) oxidation without activating de novo lipogenesis are responsible at least for the lower body fat accumulation in rats fed MLCT. The activation of hepatic lipogenesis by excessive intake of MCFA might counteract their preventive effects on body fat accumulation.
Acyl-CoA Dehydrogenase↗
Fatty acid metabolism and insulin secretion in pancreatic beta cells.
Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acyl-CoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial beta-oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states.
Animals↗