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At least 55 records · Page 3Linked to original sources
PubMed1994

Mechanisms of impaired hepatic fatty acid metabolism in rats with long-term bile duct ligation.

Hepatic metabolism of fatty acids is impaired in experimental animals with long-term bile duct ligation. To characterize the underlying defects, fatty acid metabolism was investigated in isolated hepatocytes and isolated liver mitochondria from rats subjected to long-term bile duct ligation or sham surgery. After starvation for 24 hr, the plasma beta-hydroxybutyrate concentration was decreased in rats with bile duct ligation as compared with control rats. Production of beta-hydroxybutyrate from butyrate, octanoate and palmitate by hepatocytes isolated from rats subjected to bile duct ligation was also decreased. Liver mitochondria from rats subjected to bile duct ligation showed decreased state 3 oxidation rates for L-glutamate, succinate, duroquinone, and fatty acids but not for ascorbate as substrate. State 3u oxidation rates (uncoupling with dinitrophenol) and activities of mitochondrial oxidases were also decreased in mitochondria from rats subjected to bile duct ligation. Direct assessment of the activities of the subunits of the electron transport chain revealed reduced activities of complex I, complex II and complex III in mitochondria from rats subjected to bile duct ligation. Activities of the beta-oxidation enzymes specific for short-chain fatty acids were all reduced in rats subjected to bile duct ligation. Mitochondrial protein content per hepatocyte was increased by 32% in rats subjected to bile duct ligation compared with control rats. Thus the studies directly demonstrate mitochondrial defects in fatty acid oxidation in rats subjected to bile duct ligation, which explain decreased ketosis during starvation.

3-Hydroxybutyric Acid↗
PubMed1977

Fatty acid metabolism in hypoxic rat liver.

Fatty acid metabolism was investigated in adult male albino rats exposed to hypobaric hypoxia at 25,000 ft simulated altitude for 6 h at 32 degrees C. Oxidation and esterification of palmitic acid-1-14C and de novo lipogenesis from acetate-1-14C were studied. Palmitic acid-1-14C oxidation in liver slices was normal while acetoacetate formation was increased. In vivo esterification of palmitic acid-1-14C to form triglycerides was increased while formation of phosphatidylcholine and phosphatidylethanolamine was observed to decrease. Decreased incorporation into plasma phosphatidylcholine with unaltered total activity in plasma triglycerides was observed. The incorporation of acetate-1-14C was observed to remain unaltered in triglycerides and phospholipids of liver with a similar pattern in the plasma indicating unaltered de novo lipogenesis. There appears to be increased esterification of fatty acids with probably impaired release of triglycerides into plasma while fatty acid biosynthesis remains unaffected.

Adrenal Glands↗
PubMed1999

Fatty acid metabolism in human breast cancer cells (MCF7) transfected with heart-type fatty acid binding protein.

The human breast cancer cell line MCF7 does not express heart-type fatty acid binding protein (H-FABP), a marker protein for differentiated mammary gland. MCF7 cells transfected with the bovine H-FABP cDNA expressed the corresponding protein and were characterized by growth inhibition and lower tumorgenicity in nude mice [22]. By enzyme linked immunoassay we now determined the amount of bovine H-FABP in these cells as 638 +/- 80 ng/mg protein and used the transfected cells to study the role of H-FABP in fatty acid metabolism. Compared to control cells the uptake of radioactively labelled palmitic acid and oleic acid into MCF7 cells after 30 or 60 min was increased by 67% in H-FABP expressing transfectants, demonstrating a stimulatory role for this FABP-type in fatty acid metabolism. However, preferential targeting of [14C]oleic acid into neutral or phospholipid classes was not observed by the criterion of high performance thin layer chromatography followed by autoradiography. A reason for the modest increase of fatty acid uptake in H-FABP transfected MCF7 cells may be the basal expression of epidermal-type FABP, which was detected for the first time in these cells. It appears that the small amount of E-FABP expressed in MCF7 cells fulfils the need of the cells for a cytosolic fatty acid carrier under culture conditions and that even high concentrations of another FABP do only slightly increase the uptake due to limitations of fatty acid transport through the plasma membrane or of metabolism.

Animals↗
PubMed2005

Adipose tissue fatty acid metabolism and cardiovascular disease.

PURPOSE OF REVIEW: Fatty acid and triacylglycerol metabolism in adipose tissue may be involved in the generation of risk factors for cardiovascular disease and type 2 diabetes. Pharmaceutical companies are targeting adipocyte metabolism in their search for drugs for treating, or reducing the risk of, these conditions. We review new developments in adipose tissue fatty acid metabolism and how that might relate to cardiovascular disease. RECENT FINDINGS: Fatty acid release from human adipose tissue is oscillatory, with a period of about 12 min. Remarkably, oscillatory fatty acid release is also seen in isolated adipocytes. Further evidence has emerged that not all adipose depots are equal, and that lower-body adipose tissue may exert protective effects against cardiovascular disease. There have been a number of developments in the area of fatty acid handling by adipocytes. Fatty acid binding proteins are clearly important in regulating fatty acid metabolism, with striking protection against atherosclerosis in mice deficient in both the binding proteins expressed in adipocytes. The demonstration that adipocytes lacking hormone-sensitive lipase still display lipolysis has led to the identification of novel lipases that may play crucial roles in adipose tissue fatty acid metabolism. Further evidence has accrued of the interaction between hormone-sensitive lipase and perilipin, the protein that coats the adipocyte lipid droplet. SUMMARY: Recent developments in our understanding of adipose tissue fatty acid metabolism open up the possibility of new pharmaceutical targets. However, interference with adipose tissue fatty acid metabolism is not to be undertaken lightly and needs a clear understanding of the normal role of adipocyte lipolysis.

Adipose Tissue↗
PubMed1995

Identification and quantification of intermediates of unsaturated fatty acid metabolism in plasma of patients with fatty acid oxidation disorders.

The free fatty acid and total fatty acid profiles in plasma of nine patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, two with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and two with mild-type multiple acyl-CoA dehydrogenase (MAD-m) deficiency, were analyzed by gas chromatography-mass spectrometry. In the plasma of patients with MCAD deficiency we found increases of octanoic acid (8:0), decanoic acid (10:0), 4-decenoic acid (10:1 omega 6), and 4,7-decadienoic acid (10:2 omega 3), all present almost exclusively in free form. The patients with VLCAD deficiency showed increases of mainly 5-tetradecenoic acid (14:1 omega 9) and to a minor extent 5-dodecenoic acid (12:1 omega 7), 5,8-tetradecadienoic acid (14:2 omega 6), and 7,10-hexadecadienoic acid (16:2 omega 6), in both the free and esterified fatty acid fraction. The MAD-m patients showed variable increases of all the unusual fatty acids present in MCAD- and VLCAD-deficient plasma. The 14:1 omega 9, 14:2 omega 6, and 16:2 omega 6 fatty acids were present mainly in the esterified form. Measurement of these fatty acids in plasma by the relatively simple method presented here provides a sensitive and specific aid in the diagnosis of acyl-CoA dehydrogenase deficiency disorders.

Acyl-CoA Dehydrogenase↗
PubMed1999

Abnormal fatty acid metabolism in childhood spinal muscular atrophy.

Our previous experience with abnormal fatty acid metabolism in several children with spinal muscular atrophy (SMA) prompted evaluation of fatty acid metabolism in a larger cohort. Thirty-three infants with severe infantile SMA were shown to have a significantly increased ratio of dodecanoic to tetradecanoic acid in plasma compared with normal infants and 6 infants affected with equally debilitating, non-SMA denervating disorders. Seventeen children with milder forms of SMA had normal fatty acid profiles. In addition, all 5 infants with severe SMA evaluated in a fasting state developed a distinctive and marked dicarboxylic aciduria, including saturated, unsaturated, and 3-hydroxy forms, comparable in severity with the dicarboxylic aciduria of children with primary defects of mitochondrial fatty acid beta-oxidation. Nine children with chronic SMA and 23 control patients did not develop an abnormal dicarboxylic aciduria during fasting. No known disorder of fatty acid metabolism explains all of the abnormalities we find in SMA. Our data suggest, however, that the abnormalities are not a consequence of SMA-related immobility, systemic illness, muscle denervation, or muscle atrophy. These abnormalities in fatty acid metabolism may be caused by changes in cellular physiology related to the molecular defects of the SMA-pathogenic survival motor neuron gene or neighboring genes.

Age Distribution↗
PubMed1994

Altered fatty acid metabolism in patients with angiographically documented coronary artery disease.

Plasma lipids and fatty acids have been linked to coronary artery disease (CAD), and linoleic acid deficiency has been proposed as a risk factor for cardiovascular disease, but few studies have considered their multivariate effects or found the biochemical shifts associated with abnormal fatty acid metabolism or essential fatty acid (EFA) deficiency. We studied fatty acid patterns associated with CAD using high-resolution capillary column gas-liquid chromatography to analyze fasting plasma from 47 patients with angiographically documented CAD and 56 reference subjects. CAD patients exhibited a shift in fatty acid metabolism similar to that associated with EFA-deficient patients. Compared with reference subjects, CAD patients had (1) reduced percentages of polyunsaturated fatty acids ([PUFA] 45% v 50%, P < .001), (2) increased monounsaturated fatty acids (26% v 22%, P < .001), (3) higher ratios of Mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid (0.016 v 0.013, P < .04), (4) increased levels of 16:1 omega 7 (2.10% v 1.55%, P < .001), and (5) higher concentrations of total fatty acids (356 v 284 mg/dL, P < .001), saturated fatty acids (101 v 75 mg/dL, P < .001), monounsaturated fatty acids (91 v 63 mg/dL, P < .001), PUFA (159 v 143 mg/dL, P < .01), 20:3 omega 9 (0.5 v 0.3 mg/dL, P < .01) and 16:1 omega 7 (7.7 v 4.5 mg/dL, P < .01). On indices of EFA status that depend on percentages or ratios of fatty acids or on the production of abnormal fatty acids, CAD patients were between severely EFA-deficient patients and healthy subjects, a state referred to as EFA insufficiency. Patients had metabolic shifts toward increased production of monounsaturated fatty acids and increased ratios of derivatives to precursors of omega 6 fatty acids, shifts that occur when cells are EFA-deficient. Levels of EFAs were negatively correlated with levels of saturated and monounsaturated fatty acids. The percentage of 18:2 omega 6 was positively correlated with high-density lipoprotein (HDL) cholesterol and the ratio of HDL to total cholesterol (r = .58, P < .001, and r = .61, P < .001, respectively) and negatively correlated with triglycerides and total cholesterol (r = .61, P < .001, and r = -.24, P < .01, respectively). Opposite correlations with these parameters were observed with saturated and monounsaturated fatty acids. Saturated fatty acids, total cholesterol, and indicators of EFA deficiency increased and the HDL to total cholesterol ratio and PUFA decreased the probability of CAD as measured by multivariate linear regression.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2004

Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity.

An increased diversity of therapeutic targets in the pharmaceutical industry in recent years has led to a greater diversity of toxicological effects. This, and the increased pace of drug discovery, leads to a need for new technologies for the rapid elucidation of toxicological mechanisms. As part of an evaluation of the utility of metabonomics in drug safety assessment, 1H NMR spectra were acquired on urine and liver tissue samples obtained from rats administered vehicle or a development compound (MrkA) previously shown to induce hepatotoxicity in several animal species. Multivariate statistical analysis of the urinary NMR data clearly discriminated drug-treated from control animals, due to a depletion in tricarboxylic acid cycle intermediates, and the appearance of medium chain dicarboxylic acids. High-resolution magic angle spinning NMR data acquired on liver samples exhibited elevated triglyceride levels that were correlated with changes in the urinary NMR data. Urinary dicarboxylic aciduria is associated with defective metabolism of fatty acids; subsequent in vitro experiments confirmed that MrkA impairs fatty acid metabolism. The successful application of metabonomics to characterize an otherwise ill-defined mechanism of drug-induced toxicity supports the practicality of this approach for resolving toxicity issues for drugs in discovery and development.

Animals↗
PubMed2005

RNA interference-mediated silencing of the p53 tumor-suppressor protein drastically increases apoptosis after inhibition of endogenous fatty acid metabolism in breast cancer cells.

Fatty acid synthase (FAS)-dependent endogenous fatty acid synthetic activity is abnormally elevated in a biologically-aggressive subset of breast carcinomas. Remarkably, tumor-associated FAS hyperactivity represents a novel target for anti-metabolic therapy because pharmacological inhibitors of FAS are selectively cytotoxic for tumor cells, triggering their apoptotic cell death. Since the p53 tumor-suppressor protein (TP53) is thought to play a novel role in cellular responses of a variety of non-genotoxic metabolic stresses, we characterized the involvement of TP53 in the response of breast cancer cells to FAS inhibition. MCF-7 breast cancer cells were selected for study because they have an intact TP53 pathway and undergo little apoptosis following FAS blockade. Two chemically distinct inhibitors of FAS (the natural mycotoxin cerulenin and the novel small-molecule inhibitor C75) were studied in parallel to provide a broad picture of consequences suffered by the loss of FAS function on TP53 signaling. Treatment with either cerulenin or C75 induced TP53 protein accumulation at 24 h in MCF-7 cells. To determine whether the up-regulation of TP53 following exposure to cerulenin or C75 was solely due to inhibition of endogenous fatty acid metabolism, we first evaluated the cytotoxic response to chemical FAS blockers on MCF-7 cells in which FAS gene expression was previously silenced by using the highly sequence-specific mechanism of RNA interference. MCF-7 cells became insensitive to C75-induced cytotoxicity when the expression of FAS was specifically suppressed by targeted knock-down with small interfering RNA (siRNA), whereas they partially retained their sensitivity to cerulenin. These results demonstrate that C75-induced cytotoxic damage to breast cancer cells is closely dependent on its ability to inhibit FAS-catalyzed endogenous fatty acid biogenesis, thus ruling out a significant direct effect of C75 on DNA. To determine the functional role of TP53 on breast cancer cell survival after FAS blockade, we evaluated FAS inhibitor-mediated apoptosis in MCF-7 cells transiently transfected with a pool of sequence-specific double-stranded RNA oligonucleotides targeting TP53 gene. In these conditions, TP53 protein levels were unchanged during the period of FAS-inhibitor exposure. Remarkably, siRNA-induced silencing of TP53 gene expression did result in a dramatic increase (approximately 300%) in apoptotic cell death following exposure to C75. Strikingly, there was no apparent relationship between the TP53 mutational status and sensitivity to chemical FAS inhibitor in a panel of human breast cancer cell lines. However, the degree of TP53 mRNA expression was predictive of sensitivity to C75-induced cytotoxicity, with low-TP53 mRNA expressing breast cancer cells showing hypersensitivity to FAS blockade. These findings strongly suggest that: a) TP53 is a novel molecular sensor of energy imbalance after the perturbation of endogenous fatty acid metabolism in breast cancer cells; b) TP53 function closely influences the decision between apoptosis and growth arrest following FAS blockade; and c) pharmacological inhibitors of FAS activity may be clinically useful against breast carcinomas exhibiting mutation or aberrant expression of TP53.

Apoptosis↗
PubMed1991

Intramitochondrial fatty acid metabolism: riboflavin deficiency and energy production.

Inborn errors of fatty acid beta-oxidation have contributed significantly to our understanding of intracellular fatty acid metabolism. The first intramitochondrial step in beta-oxidation of fatty acyl-CoA of different chain lengths is catalyzed by the three chain length specific acyl-CoA dehydrogenases. Inherited deficiency of these enzymes has been reported. Some are riboflavin responsive. The first step of fatty acid oxidation is reviewed with specific emphasis on beta-oxidation in newborn infants, rendered riboflavin deficient by phototherapy. Given that medium chain fatty acids are not stored as triacylglycerols and undergo rapid beta-oxidation, they have been proposed as superior substrates compared with long chain triglycerides in times of metabolic stress. This review also examines medium chain triglycerides as an alternate energy source. When medium chain triglycerides were fed as 50% of total energy, glucose sparing was present with little loss of energy as dicarboxylic acids.

Acyl-CoA Dehydrogenase↗
PubMed1979

Fatty acid metabolism in the calanoid copepod Paracalanus parvus: 1. Polyunsaturated fatty acids.

The metabolic fate of radioactive linoleate and alpha-linolenate administered to the South Atlantic copepod Paracalanus parvus was studied. The wild copepod was able to incorporate the labeled acids dissolved in seawater. The radioactive linoleate was elongated to 20:2omega6 and 22:2omega6 and desaturated by a delta6 desaturase to 18:3omega6. alpha-Linolenate was also desaturated by a delta6 desaturase to 18:4omega3 and elongated to 20:3omega3. The copepod was able to convert alpha-18:3 to 20:5omega3 and 22:6omega3.

Animals↗
PubMed1994

[Is myocardial fatty acid metabolism different between hypertrophic cardiomyopathy and hypertensive hypertrophy?].

To investigate the characteristics of fatty acid metabolism in hypertrophic cardiomyopathy (HCM), we performed myocardial imaging with 123I-iodophenyl-3-methylpentadecanoic acid (BMIPP) in 24 patients with HCM, 13 patients with hypertensive hypertrophy (HT) and 10 normal subjects. Rest myocardial imaging with 123I-BMIPP was obtained at 20 minutes and 3 hours after 123I-BMIPP injection. Rest 201Tl imaging was also performed. In addition to ordinary tomography, whole body imaging was performed to calculate % Uptake (percentage of cardiac uptake of the isotope to total injected dose). As global indexes of fatty acid metabolism, we calculated two parameters; 1) Uptake Ratio (%Uptake of 123I-BMIPP normalized by myocardial perfusion) and 2) WOR (percent reduction of myocardial 123I-BMIPP within 3 hours). Regional abnormality was evaluated by visual assessment of ordinary tomograms and by BMIPP/T1 map. BMIPP/T1 map was made from Bull's-eye maps of 123I-BMIPP and 201Tl, and it represented 123I-BMIPP uptake normalized by myocardial perfusion of each pixel which constructed the image. %Uptake of 123I-BMIPP was not different among three groups. But Uptake Ratio was significantly (p < 0.001) different among three groups; normal (1.13 +/- 0.08) > HT (1.03 +/- 0.08) > HCM (0.87 +/- 0.09). WOR of 123I-BMIPP was accelerated in HCM (12.7 +/- 4.7%) and HT (10.2 +/- 2.9%) comparing with that in normal (5.1 +/- 3.1%) (p < 0.01). In patients with HCM, by visual assessment, regional abnormality of 123I-BMIPP distribution was found in 17 of 24 patients (71%) including 3 patients with equivocal abnormality. But in patients with HT, only equivocal abnormality was observed in 23%. In BMIPP/T1 map, abnormality was observed in 92% of HCM and 8% of HT. Although global myocardial fatty acid metabolism was equally disturbed both in HCM and HT, regional abnormality of fatty acid metabolism was observed preferentially in HCM. This indicated myocardial fatty acid metabolism was not identical between HCM and HT.

Adult↗