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PubMed1997

The flux control coefficient of carnitine palmitoyltransferase I on palmitate beta-oxidation in rat hepatocyte cultures.

Two important factors that determine the flux of hepatic beta-oxidation of long-chain fatty acids are the availability of fatty acid and the activity of carnitine palmitoyltransferase I (CPT I). Using Metabolic Control Analysis, the flux control coefficient of CPT I in rat hepatocyte monolayers was determined by titration with 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate (Etomoxir), which is converted to Etomoxir-CoA, an irreversible inhibitor of CPT I. We measured CPT I activity and flux through beta-oxidation at 0.2 mM and 1.0 mM palmitate to simulate substrate concentrations in fed and fasted states. Rates of beta-oxidation were 4.5-fold higher at 1. 0 mM palmitate compared with 0.2 mM palmitate. Flux control coefficients of CPT I, estimated by two independent methods, were similar: 0.67 and 0.79 for 0.2 mM palmitate, and 0.68 and 0.77 for 1 mM palmitate. It is concluded that the regulatory potential of CPT I is similar at low and high physiological concentrations of palmitate.

Animals↗

PubMed1996

Utilization of myristic and palmitic acid in humans fed different dietary fats.

To assess the influence of dietary fat composition on the contribution of dietary myristic and palmitic acid to total fat oxidation and energy production, eight healthy men consumed diets containing 40% of total energy as fat, largely as either butter, tallow or corn oil, for 11 days. On days 8 and 11 of each diet, [1-13C]-myristic or [1-13C]-palmitic acid (20 mg kg-1 body weight) was ingested mixed with the test breakfast meal. Respiratory gas exchange was measured before, and for 9h after, consumption of the meal. Breath 13CO2 enrichments were determined hourly by isotope ratio mass spectrometry. Cumulative 9-h percentage oxidation of dietary myristic acid exceeded that of palmitic acid (P < 0.01), but neither was influenced by fat treatment [n = 8, 7.1% (1.0) (SEM), 8.6% (0.9) and 8.9% (0.6) of dietary myristic acid and 3.3% (0.7), 3.0% (0.9), and 2.5% (0.6) of dietary palmitic acid from butter, tallow and corn oil meals respectively]. Net dietary myristic acid oxidation was greater (P < 0.05) after consumption of the meal high in butter than after consumption of other fats. Net dietary palmitic acid oxidation was similar after consumption of all test meals. Precedent fat treatment had no measurable effect on net fat or carbohydrate oxidation or energy expenditure. The overall contribution of dietary myristic or palmitic acid to total fat oxidation did not exceed 1% over 9 h for any dietary fat. These results suggest that, although dietary fatty acid content is the principal determinant of net dietary fatty acid oxidation, dietary fat sources with moderate differences in fat composition do not measurably alter total energy or substrate utilization after a meal.

Adult↗

PubMed2001

Effect of palmitic acid on neutrophil functions in vitro.

BACKGROUND: It has been shown that in acne comedones the proportion of linoleic acid is markedly decreased, while palmitic acid is significantly increased. We previously reported that the decreased proportion of linoleic acid, which markedly suppresses neutrophil reactive oxygen species (ROS) generation and phagocytosis, contribute to the worsening of acne inflammation. The aim of this study was to examine the effect of palmitic acid on neutrophil functions in vitro. METHODS: We investigated the effect of palmitic acid on inflammatory parameters such as neutrophil chemotaxis, phagocytosis, and ROS generation. Reactive oxygen species generation in a cell-free, xanthine-xanthine oxidase system was also assessed. The species examined were superoxide radical anion (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH.). RESULTS: Palmitic acid significantly decreased H2O2 generation both by neutrophils and in the xanthine-xanthine oxidase system, while neutrophil chemotaxis and phagocytosis as well as O2- and OH. generation by both systems were not markedly affected in the presence of palmitic acid. CONCLUSIONS: The present study suggests that palmitic acid may be involved in the pathogenesis of acne inflammation from a standpoint of oxidative tissue injury.

Chemotaxis, Leukocyte↗

PubMed1999

Palmitate induces structural alterations in nuclei of cardiomyocytes.

The objective of this study was to examine the hypothesis that the alterations of cardiac nuclei, that has been noted in some cardiomyopathies, can be produced by palmitate, a saturated fatty acid present in high circulating concentrations in patients with conditions associated with a high probability of developing cardiomyopathy. Cardiomyocytes isolated from embryonic chick ventricle were maintained in culture for 72 h and then treated with palmitate, 100 microM for 24 h. Cells were stained with acridine orange or Giemsa and examined microscopically. Cell size and nuclear size were examined by forward light scatter during flow cytometry. Cells were permeabilized and their nuclei were stained with propidium iodide and examined by flow cytometry on populations of 10,000 cells. Cardiomyocytes treated with palmitate displayed changes in nuclear appearance as nuclei were larger, relative to cell size, with more intense acridine orange staining in a peripheral location. Nucleoli were often disrupted. Palmitate produced a significant (P < 0.001) and 17% increase in nuclear size compared to untreated cells using flow cytometry analysing forward light scatter to estimate nuclear and whole cells size. There were no significant changes in the size of the whole cell and ratio of nucleus to whole cell was significantly (P < 0.01) increased compared to control cells. Fluorescent activating cell sorting analysis of propidium iodide stained nuclei demonstrated that the nuclear enlargement was not due to cell mitosis as the proportion of nuclei in Go/G1, S or M was not changed by palmitate. In summary, these studies identify that palmitate can induce structural abnormalities of cardiomyocytes nuclei by producing increased nuclear size and nucleolar destruction.

Animals↗

PubMed2005

Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans.

Abnormalities in lipid metabolism have been proposed as contributing factors to both defective insulin secretion from the pancreatic beta cell and peripheral insulin resistance in type 2 diabetes. Previously, we have shown that prolonged exposure of isolated rat islets of Langerhans to excessive fatty acid levels impairs insulin gene transcription. This study was designed to assess whether palmitate alters the expression and binding activity of the key regulatory factors pancreas-duodenum homeobox-1 (PDX-1), MafA, and Beta2, which respectively bind to the A3, C1, and E1 elements in the proximal region of the insulin promoter. Nuclear extracts of isolated rat islets cultured with 0.5 mm palmitate exhibited reduced binding activity to the A3 and C1 elements but not the E1 element. Palmitate did not affect the overall expression of PDX-1 but reduced its nuclear localization. In contrast, palmitate blocked the stimulation of MafA mRNA and protein expression by glucose. Combined adenovirus-mediated overexpression of PDX-1 and MafA in islets completely prevented the inhibition of insulin gene expression by palmitate. These results demonstrate that prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing nuclear localization of PDX-1 and cellular expression of MafA.

Adenoviridae↗

PubMed1976

Effect of dietary palmitic acid on broiler chicks fed on various concentrations of calcium.

1. The effect of dietary palmitic acid on body weight and bone-ash of chicks fed three concentrations of calcium was studied in a 2 X 3 factorial design (0 and 10% palmitic acid, 0.4, 0.7 and 1.0% calcium). 2. Body weight of chick not influenced by the calcium concentration when palmitic acid was not included in the diet. 3. When 10% palmitic acid was included the body weight of chicks fed 0.4 and 0.7% calcium was lower (P less than 0.01) than for the other groups. 4. Bone-ash was lower (P less than 0.01) for chicks fed 0.4% calcium than for the other two calcium concentrations when palmitic acid was not added and palmitic acid at 10% of the diet reduced bone-ash of the chicks fed 0.4 and 0.7% calcium (P less than 0.01).

Animal Feed↗

PubMed2006

Ratio of oleic to palmitic acid is a dietary determinant of thrombogenic and fibrinolytic factors during the postprandial state in men.

BACKGROUND: The nature of dietary fats affects the postprandial activation of the hemostatic system. OBJECTIVE: We investigated whether the ratio of oleic to palmitic acid [and that of monounsaturated to saturated fatty acids (MUFA:SFA)] in the diet affects postprandial concentrations of triacylglycerols, tissue factor (TF), fibrinogen, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1). DESIGN: We studied the effects of diets enriched in olive oil (ROO), high-palmitic sunflower oil (HPSO), butter, or a mixture of vegetable and fish oils (VEFO) on circulating concentrations of the aforementioned factors in 14 healthy men. The fats had ratios of oleic to palmitic acid (MUFA:SFA) of 6.83 (5.43), 2.36 (2.42), 0.82 (0.48), and 13.81 (7.08). RESULTS: The largest and longest-lasting postprandial changes in plasma triacylglycerol concentrations were found with the butter-based diet (all P < 0.05). No correlation was observed between the net incremental area under the curve (netAUC) for triacylglycerol and the ratio of oleic to palmitic acid (or MUFA:SFA) in the dietary fats. The netAUCs for TF and PAI-1, however, were inversely related to the ratio of oleic to palmitic acid (and MUFA:SFA) in ROO, HPSO, butter, and VEFO. Similar results were found for the fibrinogen netAUC when VEFO was omitted from the analysis. The netAUC for t-PA was inversely correlated with postprandial concentrations of triacylglycerol. CONCLUSIONS: Postprandial concentrations of TF, fibrinogen, and PAI-1 are associated with the ratio of oleic to palmitic acid (MUFA:SFA) in dietary fats. The postprandial t-PA response is related to postprandial concentrations of triacylglycerol.

Adult↗

PubMed1997

Replacing dietary palmitic acid with elaidic acid (t-C18:1 delta9) depresses HDL and increases CETP activity in cebus monkeys.

The question whether dietary trans fatty acids affect lipoprotein metabolism similarly to specific saturated fatty acids was investigated in 11 normolipemic cebus monkeys by exchanging 5% dietary energy (%en) between elaidic (t-C18:1 delta9) and palmitic acid (16:0) in two test diets (30%en fat + 100 mg cholesterol/1000 kcal diet) conforming to the American Heart Association (AHA) Step 1 guidelines. These were compared with a normal control diet rich in saturated fat and cholesterol (38%en fat + 180 mg cholesterol/1000 kcal diet). The control diet was fed initially for 14 wk, followed by each of the the two test diets in a crossover design. Plasma lipid concentrations were determined four times between the 6th and 14th wk. Turnover studies (using 125I-HDL and 131I-LDL) were conducted after 9 wk in each dietary period. Relative to the control diet, both test diets significantly reduced plasma total cholesterol (TC), HDL cholesterol (HDL-C) and VLDL plus LDL cholesterol (LDL-C) concentrations; triglyceride (TG) concentrations tended to be lower. However, the trans diet resulted in a significantly greater reduction in HDL-C than the palmitate diet (124 +/- 17, 117 +/- 18 and 106 +/- 13 mg/dL for the control, palmitate and trans diets, respectively). The palmitate diet significantly decreased the TC/HDL-C ratio by 11% when compared with the control diet (1.68 +/- 0.17 vs. 1.89 +/- 0.30), whereas the trans diet had no effect (1.81 +/- 0.20 vs. 1.89 +/- 0.30). Kinetic studies revealed that, relative to the control diet, both test diets significantly lowered the LDL apolipoprotein B (apoB) pool size, principally reflecting an increase in the LDL apoB fractional catabolic rate (FCR) related to the reduced cholesterol intake. Between the two test diets, no significant differences in LDL kinetic parameters were observed. Both test diets significantly decreased HDL apoA1 concentrations in comparison with the control diet, which was partly explained by an increase in the fractional catabolic rate of HDL. Of the two test diets, the trans diet was associated with a 9.5% greater HDL FCR than the palmitate diet (P < 0.08) and a significant increase in plasma cholesteryl ester transfer protein (CETP) activity (% transfer 114 +/- 7 vs. 91 +/- 7; P < 0.03). Thus, palmitic acid- and elaidic acid-rich diets produced identical effects on LDL metabolism in normocholesterolemic cebus monkeys fed diets with low levels of cholesterol, whereas elaidic acid depressed HDL-C, attributable to both increased CETP activity and HDL clearance.

Animals↗

PubMed2006

Protein kinase B/Akt signalling is required for palmitate-induced beta-cell lipotoxicity.

AIM: This study was conducted to clarify cell death and survival signals in pancreatic beta-cell lipotoxicity. METHODS: Rat insulinoma INS-1 cells, with or without expression of dominant-negative mutant of Akt (K179M), were cultured with palmitate (C16:0) or oleate (C18:1) and cell numbers were determined by 0.2% eosin dye exclusion assay. The Akt activity was determined by anti-3'-phospho-inositide-dependent protein kinase (Akt)/protein kinase B (PKB) or anti-phospho-Akt (Serine 473) immunoblotting, and nuclear protein nuclear factor-kB (NF-kappaB)-binding activity was by supershift analysis. RESULTS: Twenty-four hours treatment with palmitate increased the INS-1 cell number at 0.1-0.2 mM but decreased the cell number at 0.5-1 mM. Oleate did not affect cell number at 0.1-1.0 mM. Palmitate dose-dependently increased phosphorylation of 473th serine in Akt/PKB. The K179M form of Akt/PKB abolished palmitate-induced cell proliferation at the low dose and death at the high dose. Nuclear protein NF-kappaB binding was enhanced at 0.2 and 0.5 mM of palmitate but decreased at 1.0 mM. CONCLUSION: Results suggest that Akt/PKB signalling is involved in palmitate-induced cell death and survival of pancreatic beta cell.

Animals↗

PubMed2002

Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS.

The saturated fatty acid palmitate induces apoptosis in neonatal rat cardiomyocytes. This apoptosis is associated with early mitochondrial release of cytochrome c and a subsequent loss of mitochondrial membrane potential. Recent reports implicate a role for reactive oxygen species (ROS) in palmitate-induced apoptosis. We studied the role of ROS in palmitate-induced apoptosis in the neonatal rat cardiomyocyte and report no evidence of ROS involvement. ROS production, nitric oxide production, and nuclear factor-kappaB activation were not increased above those observed using the nonapoptotic fatty acid oleate. Indeed, the production of ROS was significantly higher in cells treated with oleate. Furthermore, the presence of antioxidants and ROS scavengers did not attenuate the induction of apoptosis by palmitate. Variations in the fatty acid-to-albumin ratio from 2:1 to 7:1 had no effect on the absence of ROS production or on the extent of apoptosis. No evidence was found for an increase in oxidative protein modification in palmitate-treated cells. Our results lead us to conclude that oxidative stress does not play a role in palmitate-induced apoptosis.

Animals↗

PubMed1999

Fatty acid translocase/CD36 mediates the uptake of palmitate by type II pneumocytes.

Type II pneumocytes, which synthesize, store, and secrete pulmonary surfactant, require exogenous fatty acids, in particular palmitic acid, for maximum surfactant synthesis. The uptake of palmitate by type II pneumocytes is thought to be protein mediated, but the protein involved has not been characterized. Here we show by RT-PCR and Northern blot analysis that rat type II pneumocytes express the mRNA for fatty acid translocase (FAT/CD36), a membrane-associated protein that is known to facilitate the uptake of fatty acids into adipocytes. The deduced amino acid sequence from rat type II pneumocytes reveals 98% identity to the FAT/CD36 sequence obtained from rat adipocytes. The uptake of palmitate by type II pneumocytes follows Michaelis-Menten kinetics (Michaelis-Menten constant = 11.9 +/- 1.8 nM; maximum velocity = 62.7 +/- 5.8 pmol. min(-1). 5 x 10(5) pneumocytes(-1)) and decreases reversibly under conditions of ATP depletion to 35% of control uptake. Incubation of cells at 0 degrees C inhibited the uptake of palmitate almost completely, whereas depletion of potassium was without effect. Preincubation of the cells with bromobimane or phloretin decreases the uptake of palmitate significantly as does preincubation with sulfo-N-succinimidyl oleate, the specific inhibitor of FAT/CD36 (C. M. Harmon, P. Luce, A. H. Beth, and N. A. Abumrad. J. Membr. Biol. 121: 261-268, 1991). From these data, we conclude that FAT/CD36 is expressed in type II pneumocytes and mediates the uptake of palmitate in a saturable and energy-dependent manner. The data suggest that the uptake process is independent of the formation of coated pits and endocytotic vesicles.

Amino Acid Sequence↗

PubMed1995

Circulating palmitate uptake and oxidation are not altered by glycogen depletion in contracting skeletal muscle.

The extent to which muscle glycogen depletion affects plasma free fatty acid (FFA) metabolism in contracting skeletal muscle is not well characterized. To study this question, rats were glycogen depleted (GD) or supercompensated (SC) by swimming exercise and diet treatment 24 h before perfusion of their isolated hindquarters at rest and during electrically induced muscle contractions. After 20 min of equilibration with glucose (6 mM), palmitate (2,000 microM), and [1-14C]palmitate, palmitate uptake and oxidation were found to be similar between groups at rest and during electrical stimulation. Palmitate uptake increased by 55% during electrical stimulation and averaged 2.75 +/- 0.56 mumol.g-1.h-1. Resting palmitate oxidation averaged 0.14 +/- 0.03 mumol.g-1.h-1 and increased to 0.53 +/- 0.06 and 0.47 +/- 0.08 mumol.g-1.h-1 during electrical stimulation in GD and SC, respectively. Glucose uptake was significantly higher in GD than in SC at rest and during electrical stimulation and significantly increased in both groups during electrical stimulation to reach values of 11.8 +/- 1.2 and 7.6 +/- 1.4 mumol.g-1.h-1, respectively. Lactate release was lower in GD than in SC at rest and during electrical stimulation and was highest after 2 min of stimulation in both groups. Additional experiments at perfusate palmitate concentrations of 600-900 microM yielded similar results. These results show that, in contracting perfused skeletal muscle, muscle glycogen depletion increases glucose utilization but does not affect total plasma FFA oxidation, suggesting that regulation within pathways of carbohydrate metabolism takes precedence over regulation between pathways of lipid and carbohydrate metabolism.

Animals↗

PubMed1999

Training-induced elevation in FABP(PM) is associated with increased palmitate use in contracting muscle.

To evaluate the effects of endurance training in rats on fatty acid metabolism, we measured the uptake and oxidation of palmitate in isolated rat hindquarters as well as the content of fatty acid-binding proteins in the plasma membranes (FABP(PM)) of red and white muscles from 16 trained (T) and 18 untrained (UT) rats. Hindquarters were perfused with 6 mM glucose, 1,800 microM palmitate, and [1-(14)C]palmitate at rest and during electrical stimulation (ES) for 25 min. FABP(PM) content was 43-226% higher in red than in white muscles and was increased by 55% in red muscles after training. A positive correlation was found to exist between succinate dehydrogenase activity and FABP(PM) content in muscle. Palmitate uptake increased by 64-73% from rest to ES in both T and UT and was 48-57% higher in T than UT both at rest (39.8 +/- 3.5 vs. 26.9 +/- 4. 4 nmol. min(-1). g(-1), T and UT, respectively) and during ES (69.0 +/- 6.1 vs. 43.9 +/- 4.4 nmol. min(-1). g(-1), T and UT, respectively). While the rats were resting, palmitate oxidation was not affected by training; palmitate oxidation during ES was higher in T than UT rats (14.8 +/- 1.3 vs. 9.3 +/- 1.9 nmol. min(-1). g(-1), T and UT, respectively). In conclusion, endurance training increases 1) plasma free fatty acid (FFA) uptake in resting and contracting perfused muscle, 2) plasma FFA oxidation in contracting perfused muscle, and 3) FABP(PM) content in red muscles. These results suggest that an increased number of these putative plasma membrane fatty acid transporters may be available in the trained muscle and may be implicated in the regulation of plasma FFA metabolism in skeletal muscle.

5'-Nucleotidase↗

PubMed2006

No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise.

The systemic flux of glycerol and palmitate [a representative nonesterified free fatty acid (NEFA)] was assessed in three different phases of the menstrual cycle at rest and during moderate-intensity exercise. It was hypothesized that circulating glycerol and NEFA turnover would be greatest in the midfollicular (MF) phase of the menstrual cycle, when estrogen is elevated but progesterone low, followed by the midluteal phase (ML; high estrogen and progesterone), and lowest in the early follicular (EF) phase of the menstrual cycle (low estrogen and progesterone). Subjects included moderately active, eumenorrheic, healthy women. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting and exercise (50% maximal oxygen uptake, 90 min) measurements of tracer-determined glycerol and palmitate kinetics were made. There was a significant increase in both glycerol and palmitate turnover from rest to exercise in all phases of the menstrual cycle (P<0.0001). No significant differences, however, were observed between cycle phases in the systemic flux of glycerol or palmitate, at rest or during exercise. Maximal peripheral lipolysis during exercise, as represented by glycerol rate of appearance at 90 min, equaled 8.45+/-0.96, 8.35+/-1.12, and 7.71+/-0.96 micromol.kg-1.min-1 in the EF, MF, and ML phases, respectively. Circulating free fatty acid utilization also peaked at 90 min of exercise, as indicated by the palmitate rate of disappearance (3.31+/-0.35, 3.17+/-0.39, and 3.47+/-0.26 micromol.kg-1.min-1) in the EF, MF, and ML phases, respectively. In conclusion, systemic rates of glycerol and NEFA turnover (as represented by palmitate flux) were not significantly affected by the cyclic fluctuations in estrogen and progesterone that occur throughout the normal menstrual cycle, either at rest or during 90 min of moderate exercise.

Adult↗

PubMed1999

Glucose-induced preproinsulin gene expression is inhibited by the free fatty acid palmitate.

Prolonged exposure to elevated FFA levels has been shown to induce peripheral insulin resistance and to alter the beta-cell secretory response to glucose. To investigate the effects of FFAs on preproinsulin gene expression, we measured insulin release, cell content, and messenger RNA (mRNA) levels in rat islets after a 24-h exposure to 1 mM palmitate. Insulin release increased at all glucose concentrations studied; in contrast, preproinsulin mRNA levels were specifically reduced by palmitate at high glucose with a decrease in insulin stores, suggesting that palmitate inhibits the glucose-stimulated increase in preproinsulin gene expression. The mechanisms by which palmitate affects preproinsulin gene expression implicate both preproinsulin mRNA stability and transcription, as suggested by an actinomycin D decay assay, quantification of primary preproinsulin transcripts, and transient transfection experiments in Min6 cells. Metabolism of palmitate is not required to obtain these effects, inasmuch as they can be reproduced by 2-bromopalmitate. However, oleate and linoleate did not significantly influence preproinsulin mRNA levels. We conclude that insulin release and preproinsulin gene expression are not coordinately regulated by palmitate and that chronically elevated FFA levels may interfere with beta-cell function and be implicated in the development of noninsulin-dependent diabetes.

Animals↗

PubMed1996

Studies on [3H]palmitate-binding proteins of rat spermatozoa: a post-translational modification of membrane proteins by fatty acid acylation.

The purpose of the present study was to demonstrate the post-translational modifications of sperm plasma membrane proteins by fatty acid acylation during sperm maturation in the epididymis. Rat epididymal spermatozoa were incubated at 37 degrees C with various concentrations (100 microCi and 1 mCi) of [9-10(n)3H]palmitic acid in a medium containing Tyrode's solution supplemented with sodium bicarbonate, sodium pyruvate and sodium lactate. The incorporation of [3H]palmitate in vitro was determined in epididymal spermatozoa and an attempt was made to identify the lipid-linked proteins of purified plasma membranes of maturing epididymal spermatozoa by autoradiography. The studies demonstrated that [3H]palmitate was covalently linked to a subset of membrane cytoskeleton proteins of maturing rat spermatozoa. The pattern of incorporation of lipid was a maturation-associated phenomenon as caput spermatozoa incorporated more radioactivity than did caudal spermatozoa. The labelled proteins appeared to be membrane-bound since 82% of radioactivity was associated with membrane fractions. Autoradiograms of SDS-PAGE gels of labelled caput sperm extract showed three prominent palmitate-incorporating protein bands of about 70, 56 and 36 kDa and few minor bands. Most of these proteins were present in the membrane fraction of caput spermatozoa. Labelled gels of both the sperm extracts and of purified membranes showed resistance to hydroxylamine treatment, suggesting that there are amide bonds between lipid and proteins. The higher incorporation of labelled palmitate by immature spermatozoa of the caput epididymis compared with mature spermatozoa from the cauda epididymis and the addition of palmitate to plasma membrane proteins of caput epididymal spermatozoa suggest that fatty acylation is a post-translational modification of sperm membrane proteins.

Acylation↗

PubMed1993

Palmitate transport by rat renal basolateral membrane vesicles in the presence of albumin.

Long chain fatty acids are an important metabolic fuel for renal proximal tubules. Because of their insolubility, they are carried in the blood primarily bound to albumin. Processes involved in the cellular uptake of albumin-bound ligands are incompletely understood. To determine how fatty acids enter renal tubular cells when substrate was presented primarily bound to albumin (molar ratio albumin:palmitate = 1.0), [3H]palmitate uptake by basolateral membrane vesicles (BLMV) isolated from rat renal cortex was measured by a rapid filtration technique. The pattern of uptake was strikingly affected by buffer composition. In low-ionic-strength buffer (300 mM mannitol, 20 mM Tris-N-hydroxethylpiperazine-N'-2-ethanesulfonic acid [HEPES]), [3H]palmitate uptake plateaued in less than 1 min. The calculated volume of distribution of [3H]palmitate indicated extensive binding. In high-ionic-strength buffer with an inwardly directed NaCl, sodium gluconate, or KCl concentration gradient (100 mM) or equal intravesicular and extravesicular NaCl concentration (100 mM), uptake was biphasic with peak values 1.4- to 3-fold higher than plateau values. To test whether uptake could be specifically inhibited, phloretin (200 microM), probenecid (500 microM), or 4,4'-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS; 500 microM) was added to NaCl uptake buffer. These agents were without effect on initial uptake but inhibited the normal biphasic pattern. The biphasic uptake pattern suggested binding followed by translocation to the interior of BLMV with subsequent mediated efflux. Medicated palmitate efflux was demonstrated in BLMV preloaded with [3H]-palmitate in NaCl buffer by: (1) phloretin inhibition of efflux and (2) trans-stimulation of efflux by p-aminohippurate. Results suggest that the translocation of fatty acids derived from albumin:fatty acid complexes occurs only in the presence of high external ion concentration. Subsequent equilibration of fatty acids between albumin, BLMV, and vesicle interior is mediated by the organic anion transport system.

Animals↗

PubMed2006

Palmitate-mediated downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activation.

The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood. Previous studies have reported that insulin-resistant states are characterized by a reduction in the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1, a transcriptional activator that promotes oxidative capacity in skeletal muscle cells. However, little is known about the factors responsible for reduced PGC-1 expression. The expression of PGC-1 mRNA levels was assessed in C2C12 skeletal muscle cells exposed to palmitate either in the presence or in the absence of several inhibitors to study the biochemical pathways involved. We report that exposure of C2C12 skeletal muscle cells to 0.75 mmol/l palmitate, but not oleate, reduced PGC-1alpha mRNA levels (66%; P < 0.001), whereas PGC-1beta expression was not affected. Palmitate led to mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) 1/2 (MEK1/2) activation. In addition, pharmacological inhibition of this pathway by coincubation of the palmitate-exposed cells with the MEK1/2 inhibitors PD98059 and U0126 prevented the downregulation of PGC-1alpha. Furthermore, nuclear factor-kappaB (NF-kappaB) activation was also involved in palmitate-mediated PGC-1alpha downregulation, since the NF-kappaB inhibitor parthenolide prevented a decrease in PGC-1alpha expression. These findings indicate that palmitate reduces PGC-1alpha expression in skeletal muscle cells through a mechanism involving MAPK-ERK and NF-kappaB activation.

Animals↗