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PubMed1989

Alkylthio acetic acids (3-thia fatty acids)--a new group of non-beta-oxidizable peroxisome-inducing fatty acid analogues--II. Dose-response studies on hepatic peroxisomal- and mitochondrial changes and long-chain fatty acid metabolizing enzymes in rats.

The activity of key enzymes involved in oxidation and esterification of long-chain fatty acids was investigated after male Wistar rats were treated with different doses of sulfur substituted fatty acid analogues, 1,10-bis(carboxymethylthiodecane) (BCMTD, non-beta-oxidizable and non-omega-oxidizable), 1-mono(carboxymethylthiotetradecane) (CMTTD, trivial name, alkylthio acetic acid, non-beta-oxidizable) and 1-mono(carboxyethylthiotetradecane) (CETTD trivial name, alkylthio propionic acid, beta-oxidizable). The sulfur substituted dicarboxylic acid and the alkylthio acetic acid induced in a dose-dependent manner the mitochondrial, microsomal and especially the peroxisomal palmitoyl-CoA synthetase activity, the mitochondrial and cytosolic palmitoyl-CoA hydrolase activity, the mitochondrial and especially the microsomal glycerophosphate acyltransferase activity and the peroxisomal beta-oxidation, especially revealed in the microsomal fraction. Morphometric analysis of randomly selected hepatocytes revealed that BCMTD and CMTTD treatment increased the number, size and volume fraction of peroxisomes and mitochondria. Thus, the observed changes in the specific activity of fatty acid metabolizing enzymes with multiple subcellular localization can partly be explained as an effect of changes in the s-values of the organelles as proliferation of mitochondria and peroxisomes occurred. The most striking effect of the alkylthio propionic acid was the formation of numerous fat droplets in the liver cells and enhancement of the hepatic triglyceride level. This was in contrast to BCMTD treatment which decreased the hepatic triglyceride content. In conclusion, the results provide evidence that administration of non-beta-oxidizable fatty acid analogues had much higher in vivo potency in inducing hepatomegaly and key enzymes involved in fatty acid metabolism, including proliferation of peroxisomes and mitochondria than is exhibited in the beta-oxidizable, alkylthio propionic acid. Moreover, the dicarboxylic acid was apparently three to six times more potent than the alkylthio acetic acid in inducing peroxisomal beta-oxidation and peroxisome proliferation when considered on a mumol/day basis. As palmitic acid and hexadecanedioic acid only marginally affected these hepatic responses, it is conceivable that the potency of the selected compounds as proliferators of peroxisomes and inducers of the associated enzymes depends on their accessibility for beta-oxidation.

Acetates↗
PubMed1999

Fatty acid metabolism in marine fish: low activity of fatty acyl delta5 desaturation in gilthead sea bream (Sparus aurata) cells.

Marine fish have an absolute dietary requirement for C20 and C22 highly unsaturated fatty acids. Previous studies using cultured cell lines indicated that underlying this requirement in marine fish was either a deficiency in fatty acyl delta5 desaturase or C18-20 elongase activity. Recent research in turbot cells found low C18-20 elongase but high delta5 desaturase activity. In the present study, the fatty acid desaturase/elongase pathway was investigated in a cell line (SAF-1) from another carnivorous marine fish, sea bream. The metabolic conversions of a range of radiolabeled polyunsaturated fatty acids that comprised the direct substrates for delta6 desaturase ([1-14C]18:2n-6 and [1-14C]18:3n-3), C18-20 elongase ([U-14C]18:4n-3), delta5 desaturase ([1-14C]20:3n-6 and [U-14C]20:4n-3), and C20-22 elongase ([1-14C]20:4n-6 and [1-14C]20:5n-3) were utilized. The results showed that fatty acyl delta6 desaturase in SAF-1 cells was highly active and that C18-20 elongase and C20-22 elongase activities were substantial. A deficiency in the desaturation/elongation pathway was clearly identified at the level of the fatty acyl delta5 desaturase, which was very low, particularly with 20:4n-3 as substrate. In comparison, the apparent activities of delta6 desaturase, C18-20 elongase, and C20-22 elongase were approximately 94-, 27-, and 16-fold greater than that for delta5 desaturase toward their respective n-3 polyunsaturated fatty acid substrates. The evidence obtained in the SAF-1 cell line is consistent with the dietary requirement for C20 and C22 highly unsaturated fatty acids in the marine fish the sea bream, being primarily due to a deficiency in fatty acid delta5 desaturase activity.

Animals↗
PubMed1975

The influence of insulin on glucose and fatty acid metabolism in the isolated perfused rat hind quarter.

Glucose and fatty acid metabolism of resting skeletal muscle were studied by perfusion of the isolated rat hind leg with a hemoglobin-free medium. Tissue integrity was demonstrated by normal ATP, ADP and creatine phosphate levels, by a sufficient oxygen supply, and by a normal appearance of perfused muscle specimens under the electron microscope. The rates of glucose and fatty acid uptake, and of lactate, alanine, glycerol and fatty acid release were constant over a perfusion period of 60 min. Insulin (1 unit/l) caused a more than threefold increase in glucose uptake, a stimulation of lactate production, and a 20% increase in the muscular glycogen levels. Fatty acids and alanine release were significantly diminished by insulin, but glycerol release did not change. The uptake of oleate by the rat hind leg was dependent on the medium concentration in a range of 0.7-1.9mM oleate, and was stimulated by insulin. Glucose uptake was not influenced by oleate, whether sodium was present or not. When the leg was perfused with [1-14C]oleate, 75% of the incorporated fatty acids were found in muscle lipids, 10% were oxidized to CO2, and 5% were recovered in bone lipids. The absolute amount of oleate oxidation was not altered by insulin. In all experiments with and without glucose in the medium, 70-80% of the 14C label incorporated into muscle lipids was found in the triglyceride fraction. In the presence of glucose, insulin significantly increased the incorporation of [1-14C]oleate into muscle triglycerides, whereas no insulin effect, either on fatty acid uptake or on triglyceride formation, could be observed when glucose was omitted from the perfusate. The present results indicate that a "glucose-fatty acid cycle" as found in rat heart muscle does not operate in resting peripheral skeletal muscle tissue. They also demonstrate that the stimulating effect of insulin on muscular fatty acid uptake and triglyceride synthesis is dependent on glucose supply. This finding can be intrepreted as a stimulation of fatty acid esterification by sn-glycerol 3-phosphate derived from an increased glucose turnover, which is in turn due to insulin.

Animals↗
PubMed1997

Fatty acid metabolic imaging with iodine-123-BMIPP for the diagnosis of coronary artery disease.

UNLABELLED: Iodine-123-BMIPP kinetics under high glucose levels were examined. The feasibility of 123I-BMIPP imaging after oral glucose loading for the detection of impaired fatty acid metabolism was tested in patients with coronary artery disease. METHODS: Fatty acid metabolic imaging with 123I-BMIPP was performed on 29 patients in the fasting state and repeated after oral glucose loading. Myocardial SPECT images were obtained 20 min and 4 hr after the injection of 123I-BMIPP. Myocardial uptake of 123I-BMIPP was calculated by a Ishii-Macintyre method and the clearance of 123I-BMIPP from the myocardium was determined as (early counts-delayed counts) x 100/early counts. Regional accumulation of 123I-BMIPP was scored semiquantitatively from 0 (normal) to 4 (no activity), and the sum of regional scores in each patient was defined as a total defect score (TDS). RESULTS: Total myocardial uptake of 123I-BMIPP was 1.7% +/- 0.4% in the fasting state and 1.6% +/- 0.3% after oral glucose loading (p < 0.05). Iodine-123-BMIPP clearance from the myocardium was faster after glucose loading than in the fasting state (27% +/- 8% versus 11% +/- 6%, p < 0.01). After glucose loading, 123I-BMIPP clearance was faster in the ischemic myocardium (defined as areas perfused by stenosed coronary artery exceeding 90%) than in the nonischemic myocardium (33% +/- 8% versus 25% +/- 9%, p < 0.05). TDS in the ischemic myocardium increased from 1.8 +/- 0.4 in the fasting state to 2.1 +/- 0.4 after glucose loading (p < 0.01). The sensitivity for detecting coronary stenosis exceeding 90% increased from 55% (11/20) in the fasting state to 75% (15/20) after glucose loading without a loss of specificity (78%, 7/9). CONCLUSION: Oral glucose loading enhanced the detection of areas with impaired fatty acid metabolism due to coronary artery narrowing. Iodine-123-BMIPP imaging with oral glucose loading may be a new approach for the noninvasive diagnosis of coronary artery disease.

Adult↗
PubMed1980

Acute effects of insulin on fatty acid metabolism in isolated rat hepatocytes.

Isolated rat hepatocytes, previously shown to display enhanced rates of fatty acid biosynthesis upon a brief exposure to insulin, were used to study acute effects of this hormone on other aspects of hepatic fatty acid metabolism. Insulin activates the incorporation of exogenously added fatty acids into glycerolipids and depresses their utilization in the formation of ketone bodies. Insulin increases both the activity of acetyl-CoA carboxylase and the cellular content of malonyl-CoA. Evidence is presented that malonyl-CoA plays an important role in the insulin-mediated control of both ketogenesis and de novo fatty acid synthesis. All metabolic parameters studied are affected by glucagon in a manner opposite to that of insulin.

Acetates↗
PubMed1996

Involvement of carnitine acyltransferases in peroxisomal fatty acid metabolism by the yeast Pichia guilliermondii.

This article provides information about peroxisomal fatty acid metabolism in the yeast Pichia guilliermondii. The existence of inducible mitochondrial carnitine palmitoyltransferase and peroxisomal carnitine octanoyl-transferase activities was demonstrated after culture of this yeast in a medium containing methyl oleate. The subcellular sites and induction patterns were studied. The inhibition of carnitine octanoyl- and palmitoyl-transferases by chlorpromazine to a large extent prevented the otherwise observed metabolism-dependent inactivation of thiolase by 2-bromofatty acids in vivo. We concluded that the metabolism of long- and medium-chain fatty acids in the peroxisome of this yeast involved carnitine intermediates.

Acetyl-CoA C-Acetyltransferase↗
PubMed1988

Fatty acid metabolism and the vascular endothelial cell. New thoughts about old data.

Fatty acid metabolism by vascular endothelial cells occurs both under basal conditions and following endothelial cell stimulation or injury. Under basal conditions, endothelial cells are metabolically very active and rapidly turn over triglycerides and synthesize 13-hydroxyoctadecadienoic acid from linoleic acid via the cytosolic enzyme, omega 6-lipoxygenase. When endothelial cells are stimulated (or injured), these pathways are turned off, and, instead, arachidonic acid is liberated from the membrane phospholipids and metabolized into prostacyclin via the cyclooxygenase enzyme. The biological relevance of these two fatty acid metabolites is discussed in respect to the regulation of cell/cell interactions during both 'homeostasis' and 'injury'.

Arachidonic Acid↗
PubMedDate not supplied

Angiotensin-converting enzyme inhibitor therapy affects myocardial fatty acid metabolism after acute myocardial infarction.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor therapy has an early mortality benefit in unselected patients with acute myocardial infarction (AMI). However, the effects of ACE inhibition on myocardial fatty acid metabolism in this patient population have not been studied. We tested the hypothesis that ACE inhibitor therapy improves myocardial fatty acid metabolism and decreases mortality rate in patients after AMI. METHODS: Forty-two patients after first anterior AMI and primary angioplasty were randomly assigned to titrated oral enalapril (n = 24) or placebo therapy (n = 18). Iodine 123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) single photon emission computed tomography imaging was performed an average of 4.8 days after AMI and 1 month after AMI. BMIPP abnormalities were quantified as a severity index by a polar map. RESULTS: There were no significant changes in baseline characteristics, cardiac function, and angiographic findings between patients in the enalapril group and patients in the placebo group. However, BMIPP severity index from acute phase to chronic phase was significantly decreased in the enalapril-treated group (118+/-48 to 82+/-36, P<.05), but not in the placebo group (123+/-65 to 115+/-58, P not significant). CONCLUSION: ACE inhibition therapy improved myocardial fatty acid metabolism and regional left ventricular function in patients after anterior AMI. BMIPP single photon emission computed tomography findings imply that this better outcome may be attributable to an improvement of cellular function with ACE inhibitors.

Adult↗
PubMed2000

Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor superfamily and mediates the biological effects of peroxisome proliferators. To determine the physiological role of PPARalpha in cardiac fatty acid metabolism, we examined the regulation of expression of cardiac fatty acid-metabolizing proteins using PPARalpha-null mice. The capacity for constitutive myocardial beta-oxidation of the medium and long chain fatty acids, octanoic acid and palmitic acid, was markedly reduced in the PPARalpha-null mice as compared with the wild-type mice, indicating that mitochondrial fatty acid catabolism is impaired in the absence of PPARalpha. In contrast, constitutive beta-oxidation of the very long chain fatty acid, lignoceric acid, did not differ between the mice, suggesting that the constitutive expression of enzymes involved in peroxisomal beta-oxidation is independent of PPARalpha(.) Indeed, PPARalpha-null mice had normal levels of the peroxisomal beta-oxidation enzymes except the D-type bifunctional protein. At least seven mitochondrial fatty acid-metabolizing enzymes were expressed at much lower levels in the PPARalpha-null mice, whereas other fatty acid-metabolizing enzymes were present at similar or slightly lower levels in the PPARalpha-null, as compared with wild-type mice. Additionally, lower constitutive mRNA expression levels of fatty acid transporters were found in the PPARalpha-null mice, suggesting a role for PPARalpha in fatty acid transport and catabolism. Indeed, in fatty acid metabolism experiments in vivo, myocardial uptake of iodophenyl 9-methylpentadecanoic acid and its conversion to 3-methylnonanoic acid were reduced in the PPARalpha-null mice. Interestingly, a decreased ATP concentration after exposure to stress, abnormal cristae of the mitochondria, abnormal caveolae, and fibrosis were observed only in the myocardium of the PPARalpha-null mice. These cardiac abnormalities appeared to proceed in an age-dependent manner. Taken together, the results presented here indicate that PPARalpha controls constitutive fatty acid oxidation, thus establishing a role for the receptor in cardiac fatty acid homeostasis. Furthermore, altered expression of fatty acid-metabolizing proteins seems to lead to myocardial damage and fibrosis, as inflammation and abnormal cell growth control can cause these conditions.

Aging↗
PubMed1993

Effects of lovastatin on hepatic fatty acid metabolism.

The in vitro and in vivo effects of lovastatin on fatty acid metabolism were studied in isolated rat hepatocytes. When added in vitro to cell incubations, lovastatin stimulated de novo fatty acid synthesis and acetyl-CoA carboxylase activity, whereas fatty acid synthase activity was unaffected. Lovastatin depressed palmitate, but not octanoate, oxidation. This may be attributed to the lovastatin-induced increase in intracellular malonyl-CoA levels, as no concomitant change of carnitine palmitoyltransferase I (CPT-I) specific activity was detected. Lovastatin had no effect on the synthesis and secretion of triacylglycerols and phospholipids in the form of very low density lipoproteins (VLDL). When rats were fed a diet supplemented with 0.1% (w/w) lovastatin for one week, both acetyl-CoA carboxylase activity and de novo fatty acid synthesis were reduced compared to pair-fed controls, whereas fatty acid synthase activity was unaffected. Palmitate oxidation was enhanced in the lovastatin-fed group. There was an increase in CPT-I activity but no change in intracellular concentration of malonyl-CoA. Lovastatin feeding had no significant effect either on the esterification of exogenous palmitic acid into both cellular and VLDL triacylglycerols and phospholipids or on hepatic lipid accumulation. The in vitro and in vivo effects of lovastatin were not significantly different between periportal and perivenous hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyl-CoA Carboxylase↗
PubMed2001

The FadR.DNA complex. Transcriptional control of fatty acid metabolism in Escherichia coli.

In Escherichia coli, the expression of fatty acid metabolic genes is controlled by the transcription factor, FadR. The affinity of FadR for DNA is controlled by long chain acyl-CoA molecules, which bind to the protein and modulate gene expression. The crystal structure of FadR reveals a two domain dimeric molecule where the N-terminal domains bind DNA, and the C-terminal domains bind acyl-CoA. The DNA binding domain has a winged-helix motif, and the C-terminal domain resembles the sensor domain of the Tet repressor. The FadR.DNA complex reveals how the protein interacts with DNA and specifically recognizes a palindromic sequence. Structural and functional similarities to the Tet repressor and the BmrR transcription factors suggest how the binding of the acyl-CoA effector molecule to the C-terminal domain may affect the DNA binding affinity of the N-terminal domain. We suggest that the binding of acyl-CoA disrupts a buried network of charged and polar residues in the C-terminal domain, and the resulting conformational change is transmitted to the N-terminal domain via a domain-spanning alpha-helix.

Acyl Coenzyme A↗
PubMed1986

Myocardial fatty acid metabolism after acute ethanol consumption.

This study was undertaken to assess the effect of ethanol ingestion on myocardial fatty acid metabolism in man. Nine individuals with informed consent and with a habitual ethanol consumption of approximately 40 g per day, but without any clinical signs of heart and metabolic disease, were examined after i.v. injection of omega-123I-heptadecanoic acid (IHA). Eight days later, these individuals were similarly examined after 2 h of continuous ingestion of a body weight dependent amount of ethanol, which was calculated to produce a blood level of 100 mg per 100 ml (1%). Then the subjects had been asked to reduce their ethanol consumption rigorously for 15 months. Subsequently after 2 weeks of abstinence a follow-up investigation without ethanol loading was carried out. The investigations were performed with an Anger scintillation camera in LAO-45 degrees projection. The measurement period was 40 min. Tracer accumulation and regional elimination half-times of IHA were analysed. In all patients, acute ethanol loading produced significant changes in pattern of accumulation and/or regional elimination half-times. Ethanol-induced alterations in segmental accumulation did not appear to be predictably correlated with changes in segmental elimination half-times. After rigorous reduction of ethanol consumption followed by 2 weeks of abstinence a normalization of the tracer uptake was observed; the distribution pattern was almost homogeneous. Also the regional elimination half-times became normal. The data demonstrate the significant effects of both chronic ethanol consumption and particularly acute ethanol loading on myocardial fatty acid metabolism and the reversibility of the effects.

Adult↗
PubMed2004

Effects of selenium deficiency on fatty acid metabolism in rats fed fish oil-enriched diets.

The hepatic fatty acid metabolism was investigated in rats stressed by selenium deficiency and enhanced fish oil intake. Changes in the composition of lipids, peroxides, and fatty acids were studied in the liver of rats fed either a Sedeficient (8 microg Se/kg) or a Se-adequate (300 microg Se/kg) diet, both rich in n-3 fatty acid-containing fish oil (100 g/kg diet) and vitamin E (146 mg alpha-tocopherol/kg diet). The two diets were identical except for their Se content. Se deficiency led to a decrease in hair coat density and quality as well as to changes in liver lipids, individual lipid fractions and phospholipid fatty acid composition of the liver. The low Se status did reduce total and reduced glutathione in the liver but did not affect the hepatic malondialdehyde level. In liver phospholipids (PL), Se deficiency significantly reduced levels of palmitic acid [16:0], fatty acids of the n-3 series such as DHA [22:6 n-3], and other long-chain polyunsaturates C-20-C-22, but increased n-6 fatty acids such as linoleic acid (LA) [18:2 n-6]. Thus, the conversion of LA to arachidonic acid was reduced and the ratio of n-6/n-3 fatty acids was increased. As in liver PL, an increase in the n-6/n-3 ratio was also observed in the mucosal total fatty acids of the small intestine. These results suggest that in rats with adequate vitamin E and enhanced fish oil intake, Se deficiency affects the lipid concentration and fatty acid composition in the liver. The changes may be related to the decreased levels of selenoenzymes with antioxidative functions. Possible effects of Se on absorption, storage and desaturation of fatty acids were also discussed.

Animals↗
PubMed2002

Evaluation of free fatty acid metabolism in vivo.

In order to enable detailed studies of free fatty acid (FFA) metabolism, we recently introduced a method for the evaluation of tissue-specific FFA metabolism in vivo. The method is based on the simultaneous use of 14C-palmitate (14C-P) and the non-beta-oxidizable FFA analogue, [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP). Indices of total FFA utilization and incorporation into storage products are obtained from tissue concentrations of 3H and 14C, respectively, following intravenous administration of 3H-R-BrP and 14C-P and their disappearance from plasma into tissues. This review covers the basis for, and developments in, the methodology, as well as some of the applications to date. In the rat, the method has been used to characterize tissue-specific alterations in FFA metabolism in various situations, including skeletal muscle contraction, fasting, hyperinsulinemia, and various pharmacological manipulations. The results of all these studies clearly demonstrate tissue-level control of FFA utilization and metabolic fate, refuting the traditional view that FFA utilization is simply supply-driven. Recent developments enable the simultaneous evaluation of both tissue-specific FFA and glucose metabolism by integrating the use of 2-deoxyglucose and stable isotope-labeled glucose tracers. In conclusion, the 3H-R-BrP methodology, especially in combination with other tracers, represents a powerful tool for elucidation of tissue-specific fatty acid metabolism in vivo.

Animals↗