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[Electrocardiographic left ventricular hypertrophy without echocardiographic abnormalities evaluated by myocardial perfusion and fatty acid metabolic imaging].

The pathophysiologic process in patients with electrocardiographic left ventricular hypertrophy with ST, T changes but without echocardiographic abnormalities was investigated by myocardial perfusion imaging and fatty acid metabolic imaging. Exercise stress 99mTc-methoxy-isobutyl isonitrile (MIBI) imaging and rest 123I-beta-methyl-p-iodophenyl pentadecanoic acid (BMIPP) imaging were performed in 59 patients with electrocardiographic hypertrophy including 29 without apparent cause including hypertension and echocardiographic hypertrophy, and 30 with essential hypertension. Coronary angiography was performed in 6 patients without hypertension and 4 with hypertension and biopsy specimens were obtained from the left ventricular apex from 6 patients without hypertension. Myocardial perfusion and 123I-BMIPP images were classified into 3 types: normal, increased accumulation of the isotope at the left ventricular apex (high uptake) and defect. Transient perfusion abnormality and apical defect observed by 123I-BMIPP imaging were more frequent in patients without hypertension than in patients with hypertension (32% vs 17%, p = 0.04671 in perfusion; 62% vs 30%, p = 0.0236 in 123I-BMIPP). Eighteen normotensive patients with apical defect by 123I-BMIPP imaging included 3 of 10 patients with normal perfusion at exercise, 6 of 10 patients with high uptake and 9 of 9 patients with perfusion defect. The defect size revealed by 123I-BMIPP imaging was greater than that of the perfusion abnormality. Coronary stenoses were not observed and myocardial specimens showed myocardial disarray with hypertrophy. Moreover, 9 patients with hypertension and apical defects by 123I-BMIPP showed 3 different types of perfusion. Many patients without hypertension show a pathologic process similar to hypertrophic cardiomyopathy. Perfusion and 123I-BMIPP imaging are useful for the identification of these patients.

Biopsy↗

Effect of endothelial cell denudation on fatty acid metabolism by rabbit aorta.

The potential regulatory role of vascular endothelial cells in fatty acid uptake and metabolism by arterial tissue was studied in vitro using aortic segments from New Zealand White rabbits. Endothelium was left intact or was removed either by scraping with forceps or by rubbing with a cotton swab. Aortic segments were incubated with [14C]oleate or [14C]arachidonate, and oxidation and esterification were measured. Endothelial cell denudation by forceps or cotton swab caused a decrease in oxidation of both oleic and arachidonic acid. Esterification of oleic and arachidonic acid into phospholipid was also significantly reduced by removing the endothelium; the percent reduction was less when endothelium was removed by cotton swab than it was by forceps. Incorporation into phospholipid was reduced by cotton swab treatment, but incorporation into triglyceride was unaffected. Forceps treatment reduced oleic acid esterification into both triglyceride and phospholipid. The studies suggest that arterial endothelium has a role in fatty acid oxidation and esterification and that fatty acid utilization may be a useful metabolic index of vascular injury.

Animals↗

In vivo imaging of hepatic fatty acid metabolism in patients with non-alcoholic steatohepatitis using semiquantitative 123I-labeled branched-chain fatty acid analog.

Obesity is now prevailing worldwide, coincident with the increase of hepatic steatosis. Metabolic syndrome with obesity and hypertension, hyperlipidemia, and impaired glucose tolerance is one of the most frequent life-threatening diseases and non-alcoholic steatohepatitis is believed to be a hepatic expression of this syndrome. Non-alcoholic steatohepatitis is prevalent and well characterized in Caucasians, but little is known about non-alcoholic steatohepatitis in Asia-Oceania. Obesity will be a serious social problem in Asia-Oceania in the next two decades and we need to prevent the increase of this syndrome. Therefore, it is extremely important to know about non-alcoholic steatohepatitis based on racial differences, because this syndrome is likely to be a multi-factorial syndrome resulting from different combinations of susceptibility genes superimposed on different environmental factors. Because hepatic steatosis is the first step in the development of not only metabolic syndrome but also non-alcoholic steatohepatitis, the genetic background of Japanese NASH patients was investigated and a measure to assess fatty acid beta-oxidation in the liver in vivo was developed.

Animals↗

Myocardial fatty acid metabolism in diabetic mice with 125I-BMIPP.

In patients with diabetes mellitus, the existence of diabetic cardiomyopathy was substantiated. This study was undertaken to evaluate the myocardiac fatty acid metabolism of diabetic mice (n = 21) and controls (n = 21) in 125I-BMIPP in fasted and unfasted states. 125I-BMIPP of 370 kBq was given and thirty minutes later, animals from both groups were killed. Samples of hearts, liver and other organs were removed, weighed and then counted in a scintillation counter. The percent injected dose/g of hearts of diabetic mice was significantly reduced compared to controls in unfasted (p < 0.05) and fasted (p < 0.01) groups. These findings may reflect impaired fatty acid utilization of the hearts in diabetic mice compared to controls.

Animals↗

Effects of saturated fatty acids on n-6 fatty acid metabolism in cultured human monocyte-like cells (U937).

Effects of supplementation of saturated fatty acids (16:0 and 18:0) on metabolism of the cytotoxic n-6 fatty acids in cultured human monocyte-like cells (U937) have been examined. U937 cells were incubated in 5% delipidated fetal bovine serum containing 16:0 and 18:0. Supplementation of either 16:0 or 18:0 has no significant effect on the uptake of 18:2n-6 and 18:3n-6. However, addition of 16:0 to the medium increased whereas 18:0 suppressed the cytotoxic effects of 18:2n-6 and 18:3n-6. In addition, 16:0 supplementation reduced the incorporation of n-6 fatty acids in cellular phospholipid fraction, and enhanced the metabolism of n-6 fatty acids, particularly the conversion of 20:3n-6 to 20:4n-6 in U937 cells. Results with microsomes prepared from U937 cells also showed that 16:0 supplementation increased the delta 5 desaturase activity. This may be related in part to an increase in the availability of 20:3n-6, since results obtained in a separate study have shown that 16:0 competed with 20:3n-6 for incorporation into the phospholipid molecule at sn-2 position. Increasing the availability and formation of long chain n-6 fatty acids, which are cytotoxic, might also be responsible for increasing cytotoxicity of 16:0 supplementation.

Cell Survival↗

Essential fatty acid metabolism in cultured rat cardiomyocytes in response to either N-6 or N-3 fatty acid supplementation.

In this study we demonstrate that cultured rat cardiomyocytes possess the capacity to desaturate/elongate essential fatty acids (EFAs). Alpha-linolenic acid (ALA) conversion to higher metabolites was greater than linoleic acid (LA) conversion, according to the higher affinity of the delta-6-desaturase enzyme for the n-3 than for the n-6 EFAs. Gamma-linolenic acid (GLA) supplementation to the culture medium had no influence on LA conversion; but the addition of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids significantly decreased the formation of interconversion products from LA. The conversion of ALA to higher metabolites was greatly affected by GLA; EPA had no effect on ALA conversion, while DHA significantly inhibited it. Both GLA (converted mostly to dihomo-gamma-linolenic acid) and EPA can be removed from phospholipids and addressed to prostanoid biosynthesis, so avoiding their potential accumulation and the inhibition of their own production. Our data clearly indicate that supplementation of the culture medium with either n-6 or n-3 fatty acids can cause reduced levels of the other series of fatty acids. This effect may be undesirable, since both n-6 and n-3 fatty acids are important in the prevention of coronary diseases.

Animals↗

Assessment of myocardial fatty acid metabolism in atrioventricular synchronous pacing: analysis of iodine 123-labeled beta-methyl iodophenyl pentadecanoic acid SPECT.

BACKGROUND: We used beta-methyl iodophenyl pentadecanoic acid (BMIPP) single photon emission computed tomography (SPECT) to evaluate fatty acid metabolism in patients who were candidates for permanent pacemaker implantation and in patients with atrioventricular (AV) synchronous pacing. METHODS AND RESULTS: We performed BMIPP SPECT studies in 66 patients with bradyarrhythmia, of whom 11 patients were candidates for permanent pacemaker implantation, 27 patients had atrial pacing (atrial sensing, inhibited mode, simple programmable [AAI]), and 28 patients had atrial synchronous ventricular inhibited pacing (ventricular pacing, 2-chamber sensing, atrial-triggered and ventricular-inhibited, multiprogrammable [VDD]) or atrial and ventricular pacing in sequence (atrial and ventricular sensing, atrial-inhibited and atrial-triggered, ventricular-inhibited, multiprogrammable [DDD]). A qualitative assessment revealed that the BMIPP uptake at the septal, inferior, and apical regions was significantly decreased in the patients with VDD/DDD compared with both the candidates for permanent pacemaker implantation and the patients with AAI. The total extent score (ES) and severity score (SS) were significantly higher in the patients with VDD/DDD than in the other 2 groups. Significant regional differences of both ES and SS values were observed at the septal and inferior regions in the patients with VDD/DDD compared with the other groups. No differences were found between the qualitative and quantitative measures of BMIPP uptake in the candidates for permanent pacemaker implantation and those in the patients with AAI. CONCLUSION: Our study suggests that AV synchronous right ventricular pacing resulting in the delayed conduction and depolarization of myocardial cells may directly interfere with regional cellular free fatty acid uptake and metabolism.

Aged↗

Insulin and non-esterified fatty acid metabolism in asymptomatic diabetics and atherosclerotic subjects.

Glucose, insulin and non-esterified fatty acid (NEFA) metabolism was studied in 18 patients (mean age 49) with ischemic heart disease (IHD) who did not have any concurrent disorder known to affect glucose tolerance.Significant hyperglycemia and hyperinsulinemia were observed in the IHD patients after oral glucose. The serum NEFA declined to a lower level in IHD patients than in normal subjects who received glucose.In response to hypoglycemia following the oral administration of sodium tolbutamide the serum NEFA in IHD patients rose to a higher level in the rebound phase than in normal subjects. This rise was preceded by a sharp decline in the concentration of circulating insulin.In 72% of the patients (IHD sub-group) the blood glucose values after oral glucose satisfied the criteria for the diagnosis of diabetes mellitus. The metabolic changes following oral glucose in the IHD sub-group and in asymptomatic diabetics (AD), free of clinical atherosclerosis and with similar impairment in glucose tolerance, were compared. Despite insignificantly lower insulin concentrations, the AD showed a significantly lesser fall in circulating NEFA than did the patients in the IHD sub-group. After oral sodium tolbutamide the IHD sub-group patients showed a greater insulin response and a greater rebound increase in circulating NEFA than did the AD.These differences in response to oral glucose and to sodium tolbutamide suggest that the pathogenesis of the impaired glucose tolerance in IHD may be different from that responsible for abnormal carbohydrate tolerance in asymptomatic diabetics without evident atherosclerosis. The abnormalities demonstrated in glucose, insulin and NEFA metabolism may play a role in the genesis of the hyperlipoproteinemia and atherosclerosis of IHD. One possible mechanism leading to hyperlipoproteinemia in ischemic heart disease compatible with the data is discussed.

Arteriosclerosis↗

Fatty acid metabolism by the porcine placenta.

Two experiments were performed to determine whether esterification is a major pathway of fatty acid utilization within porcine placenta and to determine what metabolic parameters may limit fatty acid transfer to the fetal pig. Maternal (endometrium) and fetal (chorioallantois) placenta were obtained by Caesarean section at d 110 of gestation in both experiments. Eight gilts were used in the first experiment. Tissue sections were incubated with palmitate at concentrations ranging from .25 to 2.0 mM. Maternal placenta metabolized palmitate at a higher rate than fetal placenta, although fetal placenta was more efficient in esterifying palmitate. Esterification composed the majority of palmitate utilization within fetal and maternal placenta. The second experiment evaluated the effect of dietary lipid on placental fatty acid metabolism and evaluated the ability of placenta to mobilize lipids. Fourteen gilts were divided into two groups of seven and fed a diet containing 15% tallow diet or a diet not supplemented with tallow (control) from d 90 to 110 of gestation. Dietary lipid had no detectable effects on lipoprotein lipase activity, [14C]palmitate metabolism, or lipolysis by the maternal or fetal placenta. Lipolytic activity of placental tissues was minimally affected by incubation with various proposed lipolytic activity of placental tissues was minimally affected by incubation with various proposed lipolytic agents. The data indicate that supply of fatty acids to the fetal pig may be limited by transfer of plasma fatty acids into the cytoplasm of placental cells or by regulatory enzymes for intermediate esterification; both types of limitations have been proposed to be influenced by fatty-acid binding proteins.

Animals↗

Effects of oral contraceptives on free fatty acid metabolism in women.

These studies examined whether women using oral contraceptives have abnormalities in free fatty acid (FFA) metabolism compared with women not using oral contraceptives. Plasma palmitate kinetics ([3H]palmitate) were measured at rest, following glucose ingestion, and during epinephrine infusion in 13 oral contraceptive users and 13 matched women not using oral contraceptives. Oral contraceptive users had significantly greater plasma triglyceride concentrations and glucose responses to oral glucose tolerance testing. No differences in basal (2.1 +/- 0.1 v 1.8 +/- 0.2 micromol x kg fat-free mass x FFM(-1) x min[-1]), glucose-suppressed (0.6 +/- 0.1 v 0.5 +/- 0.1 micromol x kg FFM(-1) x min[-1]), or epinephrine-stimulated (3.3 +/- 0.1 v 3.6 +/- 0.2 micromol x kg FFM(-1) x min[-1]) palmitate flux were detected between women using and not using oral contraceptives. The respiratory quotient (RQ) also was not different between groups. We conclude that the increase in plasma triglycerides and the mild glucose intolerance seen with oral contraceptive use is not associated with significant abnormalities of FFA metabolism.

Adult↗

Dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of malonyl-CoA.

AIMS/HYPOTHESIS: An elevated lipid content within skeletal muscle cells is associated with the development of insulin resistance and type 2 diabetes mellitus. We hypothesised that in subjects with type 2 diabetes muscle malonyl-CoA (an inhibitor of fatty acid oxidation) would be elevated at baseline in comparison with control subjects and in particular during physiological hyperinsulinaemia with hyperglycaemia. Thus, fatty acids taken up by muscle would be shunted away from oxidation and towards storage (non-oxidative disposal). MATERIALS AND METHODS: Six control subjects and six subjects with type 2 diabetes were studied after an overnight fast and during a hyperinsulinaemic (0.5 mU kg(-1) min(-1)), hyperglycaemic clamp (with concurrent intralipid and heparin infusions) designed to increase muscle malonyl-CoA and inhibit fat oxidation. We used stable isotope methods, femoral arterial and venous catheterisation, and performed muscle biopsies to measure palmitate kinetics across the leg and muscle malonyl-CoA. RESULTS: Basal muscle malonyl-CoA concentrations were similar in control and type 2 diabetic subjects and increased (p<0.05) in both groups during the clamp (control, 0.14+/-0.05 to 0.24+/-0.05 pmol/mg; type 2 diabetes, 0.09+/-0.01 to 0.20+/-0.02 pmol/mg). Basal palmitate oxidation across the leg was not different between groups at baseline and decreased in both groups during the clamp (p<0.05). Palmitate uptake and non-oxidative disposal were significantly greater in the type 2 diabetic subjects at baseline and during the clamp (p<0.05). CONCLUSIONS/INTERPRETATION: Contrary to our hypothesis, the dysregulation of muscle fatty acid metabolism in type 2 diabetes is independent of muscle malonyl-CoA. However, elevated fatty acid uptake in type 2 diabetes may be a key contributing factor to the increase in fatty acids being shunted towards storage within muscle.

Adult↗

[Assessment of myocardial fatty acid metabolism in patients with angina pectoris and diabetes mellitus using 123I-BMIPP myocardial scintigraphy].

PURPOSE: We studied the effect of myocardial ischemia and diabetes mellitus (DM) on the myocardial fatty acid metabolism using 123I-BMIPP myocardial scintigraphy. METHODS: We performed 123I-BMIPP myocardial scintigraphy in 50 patients with myocardial ischemia and without DM (AP), in 30 patients with myocardial ischemia and DM (AP + DM), 12 patients with DM and without myocardial ischemia (DM), and in 10 normal subjects (N). Myocardial uptake rate of 123I-BMIPP was obtained using the time activity curve. Myocardial washout rate of 123I-BMIPP was calculated using the polar images of early and delayed SPECT images. RESULTS: Myocardial uptake rate of 123I-BMIPP (%) were AP: 4.9 +/- 0.6, AP + DM: 5.5 +/- 0.5, DM 5.7 +/- 0.5 and N: 5.0 +/- 0.4. 123I-BMIPP myocardial uptake rate was increased in AP + DM and DM. 123I-BMIPP myocardial washout rate (%) were AP: 30.2 +/- 4.3, AP + DM: 24.5 +/- 3.9, DM: 16.1 +/- 2.8 and N: 19.4 +/- 3.2. 123I-BMIPP myocardial washout rate was increased in AP and AP + DM. 123I-BMIPP myocardial washout rate was increased particularly in patients with multi-vessels disease. 123I-BMIPP myocardial washout rate was decreased in DM. CONCLUSION: The present study suggested that diabetes mellitus increased myocardial fatty acid uptake and decreased myocardial fatty acid washout, and that myocardial ischemia increased myocardial fatty acid washout.

Aged↗

Genetic connection between fatty acid metabolism and sporulation in Aspergillus nidulans.

In the Ascomycete fungus Aspergillus nidulans, the ratio of conidia (asexual spores) to ascospores (sexual spores) is affected by linoleic acid moieties including endogenous sporogenic factors called psi factors. Deletion of odeA (Delta odeA), encoding a Delta-12 desaturase that converts oleic acid to linoleic acid, resulted in a strain depleted of polyunsaturated fatty acids (18:2 and 18:3) but increased in oleic acid (18:1) and total percent fatty acid content. Linoleic acid-derived psi factors were absent in this strain but oleic acid-derived psi factors were increased relative to wild type. The Delta odeA strain was reduced in conidial production and mycelial growth; these effects were most noticeable when cultures were grown at 26 degrees C in the dark. Under these environmental conditions, the Delta odeA strain was delayed in ascospore production but produced more ascospores than wild type over time. This suggests a role for oleic acid-derived psi factors in affecting the asexual to sexual spore ratio in A. nidulans. Fatty acid composition and spore development were also affected by veA, a gene previously shown to control light driven conidial and ascospore development. Taken together our results indicate an interaction between veA and odeA alleles for fatty acid metabolism and spore development in A. nidulans.

Aspergillus↗

Effects of proglycosyn (LY177507) on fatty acid metabolism in rat hepatocytes.

Proglycosyn (LY177507) belongs to a series of powerful agents that stabilize liver glycogen stores by promoting glycogen synthesis from different precursors and inhibiting glycogenolysis and glycolysis. In the present study we have examined the effects of proglycosyn on fatty acid metabolism in isolated hepatocytes. Preincubation of hepatocytes with medium containing proglycosyn led to a marked inhibition of fatty acid synthesis de novo and acetyl-CoA carboxylase activity without affecting fatty acid synthase. Likewise, proglycosyn depressed the synthesis of triacylglycerols and phospholipids from labeled palmitate. Although octanoate oxidation was unaffected by proglycosyn, mitochondrial palmitate oxidation was notably stimulated. This effect may be attributed to the proglycosyn-induced decrease of intracellular malonyl-CoA levels relative to control incubations and the concomitant relieve of the inhibition of the mitochondrial-outer-membrane carnitine palmitoyl-transferase by malonyl-CoA. By contrast, neither peroxisomal palmitate oxidation nor peroxisomal carnitine palmitoyltransferase activity was changed upon hepatocyte incubation with proglycosyn. Results thus indicate that proglycosyn increases the fatty-acid-oxidation efficiency of the liver at the expense of lipogenesis, and this may contribute to the proglycosyn-induced sparing of liver glycogen stores.

Acetyl-CoA Carboxylase↗

The effects of alkylthioacetic acids (3-thia fatty acids) on fatty acid metabolism in isolated hepatocytes.

Long-chain alkylthioacetic acids (3-thia fatty acids) inhibit fatty acid synthesis from [1-14C]acetate in isolated hepatocytes, while fatty acid oxidation is nearly unaffected or even stimulated. Desaturation of [1-14C]stearate (delta 9-desaturase) is also unaffected. [1-14C]Dodecylthioacetic acid (a 3-thia fatty acid) is incorporated in triacylglycerol and in phospholipids more efficiently than [1-14C]palmitate in isolated hepatocytes. The metabolism of [1-14C]dodecylthioacetic acid to acid-soluble products (by omega-oxidation) is slow compared to the oxidation of [1-14C]palmitate. In hepatocytes from adapted rats (rats fed tetradecylthioacetic acid for 4 days) the rate of [1-14C]palmitate oxidation is increased and its rate of esterification is decreased. Stearate desaturation is also decreased. The rate of cyanide-insensitive peroxisomal fatty acid beta-oxidation is several-fold increased. The metabolic effects of long-chain 3-thia fatty acids are discussed and it is concluded that they behave essentially like normal fatty acids except for their slow breakdown due to the sulfur atom in the 3 position, which blocks normal beta-oxidation.

Acetates↗