Accumulation Of Palmitic Acid Research Articles

Downregulation of sirtuin 3 by palmitic acid increases the oxidative stress, impairment of mitochondrial function, and apoptosis in liver cells.

Elevated levels of saturated fatty acids show a strong cytotoxic effect in liver cells. Sirtuin 3 (SIRT3), a mitochondrially localized member of NAD+ -dependent deacetylase has been shown to protect hepatocytes against the oxidative stress. The role of SIRT3 on the cytotoxicity caused by fatty acids in liver cells is not fully understood. The aim of this study was to evaluate the expression level of SIRT3, oxidative stress, and mitochondrial impairments in human hepatoma HepG2 cells exposed to palmitic acid (PA). Our results showed that PA treatment caused the deposition of lipid droplets and resulted in an increased expression of tumor necrosis factor-α in a dose-dependent manner. Excessive accumulation of PA induces the reactive oxygen species formation and apoptosis while dissipating the mitochondrial transmembrane potential. The level of SIRT3 expression in both nuclear and mitochondrial fractions in HepG2 cells was decreased with the increase in PA concentrations. However, in the cytosolic fraction, the SIRT3 was undetectable. In conclusion, our results showed that PA caused an increase in inflammation and oxidative stress in HepG2 cells. The exposure of PA also resulted in the decline in transmembrane potential and an increase in apoptosis. The underexpression of nuclear and mitochondrial SIRT3 by PA suggests that the PA target the process that regulates the stress-related gene expression and mitochondrial functions.

Adaptive changes in saturated fatty acids as a resistant mechanism in salt stress in Halomonas alkaliphila YHSA35

SINCE salinity is one of the major abiotic stresses, bacteria totally have different adaptive or tolerant mechanisms that respond to salinity stress. Multiwavelength UV-Vis spectroscopy used to estimate the bacterial growth under different sodium chloride concentrations. Absorbance ratio of 280nm to 260nm (A280/A260) varied considerably according to the salt concentration. This showed some metabolic activity changes as a part of the adaptive response that allows Halomonas alkaliphila to face salinity stress changes. Here, adaptive changes of fatty-acid composition of H. alkaliphila YHSA35 because of different sodium chloride concentrations were determined. In this work, fatty acids methyl esters (FAME) composition analysis was achieved and estimated the presence of thirty-four fatty acids in H. alikaliphila YHSA35 cells. Quantitatively changes were found within the level of saturated fatty acids; Caproic, Lauric, Undecanoic, Myristic, Palmitic, Heptadecanoic and in unsaturated fatty acids; Oleic, cis-11-Eicosenoic, Erucic. In high salt concentration, unsaturated fatty acids synthesis rate is reduced, resulting in an accumulation of palmitic acid. In conclusion, levels of saturated fatty acid profile changed in H. alkaliphila YHSA35 because of salinity stress that may modulate the membrane lipid viciousness for adaptation and best cellular perform.

The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

Inhibition of ERK1/2 downregulates triglyceride and palmitic acid accumulation in cashmere goat foetal fibroblasts

ABSTRACTAn extracellular signal-regulated kinase (ERK) is a mitogen-activated protein kinase (MAPK) in mammalian cells that interact with the mechanistic target of rapamycin (mTOR) signalling pathway. ERK signalling integrates signals from growth factors, nutrients, and mitogens to regulate cell proliferation, differentiation, and the cell cycle. The purpose of this study was to examine the inhibitory effects of U0126, a specific MEK/ERK inhibitor, on ERK and mTOR signalling, Lipin 1 protein level, PPARγ activation, and triglyceride (TAG) and palmitic acid (PA) accumulation in Cashmere goat foetal fibroblasts (GFbs). The proliferation of GFbs was significantly impeded by U0126, the IC50 of which was 1.54 µM. U0126 prevented the phosphorylation of ERK1/2 (Thr202/Tyr204), S6 (Ser240/244), and 4EBP1 (Thr37/46), the latter 2 of which are mTOR downstream effectors. Moreover, the cytoplasmic level of Lipin 1 and the nuclear PPARγ protein abundance were attenuated by U0126 while the concentration of TAG and PA was significantly decreased (p < .05) in GFbs. These data indicate that ERK1/2 have important functions in GFb proliferation, governing the activation of PPARγ and Lipin 1 level and the accumulation of TAG and PA.

A High-fat Diet Promotes Depression-like Behavior in Mice by Suppressing Hypothalamic PKA Signaling

Obesity is associated with an increased risk of depression. The aim of the present study was to investigate whether obesity is a causative factor for the development of depression and what is the molecular pathway(s) that link these two disorders. Using lipidomic and transcriptomic methods we identified a mechanism that links exposure to a high-fat diet (HFD) in mice with alterations in hypothalamic function that lead to depression. Consumption of an HFD selectively induced accumulation of palmitic acid in the hypothalamus, suppressed the 3´, 5´-cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and increased the concentration of free-fatty acid receptor 1 (FFAR1). Deficiency of phosphodiesterase 4A (PDE4A), an enzyme that degrades cAMP and modulates stimulatory regulative G-protein (Gs)-coupled G protein-coupled receptor signaling, protected animals either from genetic- or dietary induced depression phenotype. These findings suggest that dietary intake of saturated fats disrupts hypothalamic functions by suppressing cAMP/PKA signaling through activation of PDE4A. FFAR1 inhibition and/or an increase of cAMP signaling in the hypothalamus could offer potential therapeutic targets to counteract the effects of dietary or genetically induced obesity on depression.

Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications.

Palmitic acid (PA) has been for long time negatively depicted for its putative detrimental health effects, shadowing its multiple crucial physiological activities. PA is the most common saturated fatty acid accounting for 20–30% of total fatty acids in the human body and can be provided in the diet or synthesized endogenously via de novo lipogenesis (DNL). PA tissue content seems to be controlled around a well-defined concentration, and changes in its intake do not influence significantly its tissue concentration because the exogenous source is counterbalanced by PA endogenous biosynthesis. Particular physiopathological conditions and nutritional factors may strongly induce DNL, resulting in increased tissue content of PA and disrupted homeostatic control of its tissue concentration. The tight homeostatic control of PA tissue concentration is likely related to its fundamental physiological role to guarantee membrane physical properties but also to consent protein palmitoylation, palmitoylethanolamide (PEA) biosynthesis, and in the lung an efficient surfactant activity. In order to maintain membrane phospholipids (PL) balance may be crucial an optimal intake of PA in a certain ratio with unsaturated fatty acids, especially PUFAs of both n-6 and n-3 families. However, in presence of other factors such as positive energy balance, excessive intake of carbohydrates (in particular mono and disaccharides), and a sedentary lifestyle, the mechanisms to maintain a steady state of PA concentration may be disrupted leading to an over accumulation of tissue PA resulting in dyslipidemia, hyperglycemia, increased ectopic fat accumulation and increased inflammatory tone via toll-like receptor 4. It is therefore likely that the controversial data on the association of dietary PA with detrimental health effects, may be related to an excessive imbalance of dietary PA/PUFA ratio which, in certain physiopathological conditions, and in presence of an enhanced DNL, may further accelerate these deleterious effects.

Phycocyanin-Functionalized Selenium Nanoparticles Reverse Palmitic Acid-Induced Pancreatic β Cell Apoptosis by Enhancing Cellular Uptake and Blocking Reactive Oxygen Species (ROS)-Mediated Mitochondria Dysfunction.

Accumulation of palmitic acid (PA) in human bodies could cause damage to pancreatic β cells and lead to chronic diseases by generation of reactive oxygen species (ROS). Therefore, it is of great significance to search for nutrition-available agents with antioxidant activity to protect pancreatic islet cells against PA-induced damage. Phycocyanin (PC) and selenium (Se) have been reported to have excellent antioxidant activity. In this study, PC-functionalized selenium nanoparticles (PC-SeNPs) were synthesized to investigate the in vitro protective effects on INS-1E rat insulinoma β cells against PA-induced cell death. A potent protective effect was achieved by regulation of particle size and PC content. Among three PC-SeNPs (165, 235, and 371 nm), PC-SeNPs-235 nm showed the highest cellular uptake and the best protective activities. For cell cycle analysis, PC-SeNPs showed a better protective effect on PA-induced INS-1E cell apoptosis than PC or SeNPs, and PC-SeNPs-235 nm exhibited the best effect. Further mechanistic studies demonstrated that PA induced overproduction of intracellular ROS, mitochondria fragmentation, activation of caspase-3, -8, and -9, and cleavage of PARP. However, pretreatment of the cells with PC-SeNPs effectively blocked these intracellular events, which suggests that PC-SeNPs could protect INS-1E cells against PA-induced cell apoptosis via attenuating oxidative stress and downstream signaling pathways. This finding provides a great promising nutritional approach for protection against diseases related to islet damage.

Genetic enhancement of palmitic acid accumulation in cotton seed oil through RNAi down-regulation of ghKAS2 encoding β-ketoacyl-ACP synthase II (KASII).

SummaryPalmitic acid (C16:0) already makes up approximately 25% of the total fatty acids in the conventional cotton seed oil. However, further enhancements in palmitic acid content at the expense of the predominant unsaturated fatty acids would provide increased oxidative stability of cotton seed oil and also impart the high melting point required for making margarine, shortening and confectionary products free of trans fatty acids. Seed‐specific RNAi‐mediated down‐regulation of β‐ketoacyl‐ACP synthase II (KASII) catalysing the elongation of palmitoyl‐ACP to stearoyl‐ACP has succeeded in dramatically increasing the C16 fatty acid content of cotton seed oil to well beyond its natural limits, reaching up to 65% of total fatty acids. The elevated C16 levels were comprised of predominantly palmitic acid (C16:0, 51%) and to a lesser extent palmitoleic acid (C16:1, 11%) and hexadecadienoic acid (C16:2, 3%), and were stably inherited. Despite of the dramatic alteration of fatty acid composition and a slight yet significant reduction in oil content in these high‐palmitic (HP) lines, seed germination remained unaffected. Regiochemical analysis of triacylglycerols (TAG) showed that the increased levels of palmitic acid mainly occurred at the outer positions, while C16:1 and C16:2 were predominantly found in the sn‐2 position in both TAG and phosphatidylcholine. Crossing the HP line with previously created high‐oleic (HO) and high‐stearic (HS) genotypes demonstrated that HP and HO traits could be achieved simultaneously; however, elevation of stearic acid was hindered in the presence of high level of palmitic acid.

Changes in Chemical Composition, Total Phenolics and Antioxidant Activity of Alpinia (&lt;i&gt;Alpinia zerumbet&lt;/i&gt;) Leaves Exposed to UV

Alpinia zerumbet (Pers.) B.L. Burtt. &amp; R.M. Sm is an important perennial ginger plant in the tropics with various uses as foods, dietary supplement, cosmetics, essential oil production and traditional medicines. In this study, essential oils, phenolic acids, fatty acids, kavains, total phenols and antioxidant activity in A. zerumbet plants exposed to UV-C were investigated. Number and weights of essential oils increased rapidly from 1 to 3 days of exposure. Major extend of essential oils was recorded in methyl cinnamate and followed by benzyl acetone. The correspondence to the accumulation of palmitic acid was 15 folds, in contrast to the strong reduction of stearic quantity was 10 folds at 3 days of treatment. Changes in chemical components and antioxidant capacity in A. zerumbet are differed reversely between the exposure of UV-C and heavy toxic chemicals. The exposure of UV-C is beneficial for the increasing of essential oil production in A. zerumbet.

Changes in Chemical Composition, Total Phenolics and Antioxidant Activity of Alpinia (&lt;i&gt;Alpinia zerumbet&lt;/i&gt;) Leaves Exposed to UV

Alpinia zerumbet (Pers.) B.L. Burtt. &amp; R.M. Sm is an important perennial ginger plant in the tropics with various uses as foods, dietary supplement, cosmetics, essential oil production and traditional medicines. In this study, essential oils, phenolic acids, fatty acids, kavains, total phenols and antioxidant activity in A. zerumbet plants exposed to UV-C were investigated. Number and weights of essential oils increased rapidly from 1 to 3 days of exposure. Major extend of essential oils was recorded in methyl cinnamate and followed by benzyl acetone. The correspondence to the accumulation of palmitic acid was 15 folds, in contrast to the strong reduction of stearic quantity was 10 folds at 3 days of treatment. Changes in chemical components and antioxidant capacity in A. zerumbet are differed reversely between the exposure of UV-C and heavy toxic chemicals. The exposure of UV-C is beneficial for the increasing of essential oil production in A. zerumbet.

Design of Expression Cassettes for Inverted Repeat and Intron-Spliced Inverted Repeat of PATE Gene Silencing

Palm oil of Elaeis guineensis Jacq. contains approximately 50% saturated and 50% unsaturated fatty acids. In the composition of saturated fatty acid, palmitic acid is the most abundant which is predominantly around 44% of the total fatty acids. The high level of accumulation of palmitic acid should be reduced in order to get a better dietary fatty acid and a more nutritional value oil in the market.The purpose in reducing palmitic acid content could be carried out by silencing palmitoyl-ACP thioesterase (PATE) gene activities. Primer pairs to amplify partial PATE fragments, intron and 3Untranslated Region (3UTR) were designed from PATE of Elaeis guineensis var tenera (GenBank DQ422858). PATE fragments, intron and 3UTR were constructed in two expression cassettes with inverted repeat (IR) and intron-spliced inverted repeat (ISIR) orientations to generate hair-pin RNAs (hpRNA). Combinations of restriction enzymes (RE) were used to confirm, the size, orientation and location of the inserts.

Fatty Acid Binding Protein 3 Is Involved in n–3 and n–6 PUFA Transport in Mouse Trophoblasts

Background:Low placental fatty acid (FA) transport during the embryonic period has been suggested to result in fetal developmental disorders and various adult metabolic diseases, but the molecular mechanism by which FAs are transported through the placental unit remains largely unknown. Objective:The aim of this study was to examine the distribution and functional relevance of FA binding protein (FABP), a cellular chaperone of FAs, in the mouse placenta. Methods:We clarified the localization of FABPs and sought to examine their function in placental FA transport through the phenotypic analysis of Fabp3-knockout mice. Results:Four FABPs (FABP3, FABP4, FABP5, and FABP7) were expressed with spatial heterogeneity in the placenta, and FABP3 was dominantly localized to the trophoblast cells. In placentas from the Fabp3-knockout mice (both sexes), the transport coefficients for linoleic acid (LA) were significantly reduced compared with those from wild-type mice by 25% and 44% at embryonic day (E) 15.5 and E18.5, respectively, whereas those for α-linolenic acid (ALA) were reduced by 19% and 17%, respectively. The accumulation of LA (18% and 27% at E15.5 and E18.5) and ALA (16% at E15.5) was also significantly less in the Fabp3-knockout fetuses than in wild-type fetuses. In contrast, transport and accumulation of palmitic acid (PA) were unaffected and glucose uptake significantly increased by 23% in the gene-ablated mice compared with wild-type mice at E18.5. Incorporation of LA (51% and 52% at 1 and 60 min, respectively) and ALA (23% at 60 min), but not PA, was significantly less in FABP3-knockdown BeWo cells than in controls, whereas glucose uptake was significantly upregulated by 51%, 50%, 31%, and 33% at 1, 20, 40, and 60 min, respectively. Conclusions:Collectively FABP3 regulates n–3 (ω-3) and n–6 (ω-6) polyunsaturated FA transport in trophoblasts and plays a pivotal role in fetal development.

Multiple pathways are involved in palmitic acid-induced toxicity

In this study, we identified the toxic mechanism following the accumulation of palmitic acid (PA), a saturated fatty acid, in human Chang liver cells. After PA exposure for 24h, the mitochondria and the endoplasmic reticulum (ER) became dilated, and lipid droplets and organelles were observed within autophagosomes. Cell viability decreased with an ATP reduction and the G2/M phase arrest. The expression of SOD-2, but not of SOD-1, markedly increased after PA exposure, which also elevated the number of cells generating ROS. PA enhanced the levels of proteins related to apoptosis, necroptosis, autophagy, and ER stress. Moreover, the inhibition of caspases, p53, necroptosis, or ER stress substantially rescued PA-induced cytotoxicity and, similarly, the inhibition of caspases and ER stress counteracted PA-induced changes in the cell cycle. Conversely, the inhibition of necroptosis and p53 signaling accelerated the changes in the cell cycle triggered by PA exposure. Blocking autophagy exacerbated PA-induced cytotoxicity and alterations in the cell cycle and caused disappearance of cellular components. These results suggest that PA induces apoptosis accompanied by autophagy through mitochondrial dysfunction and ER stress, which are triggered by oxidative stress in Chang liver cells and that blocking autophagy accelerates cell damage following PA exposure.

Sterol regulatory element-binding protein-1c mediates increase of postprandial stearic acid, a potential target for improving insulin resistance, in hyperlipidemia.

Elevated serum free fatty acids (FFAs) levels play an important role in the development of insulin resistance (IR) and diabetes. We investigated the dynamic changes and the underlying regulatory mechanism of postprandial FFA profile in hyperlipidemia (HLP) and their relation with insulin sensitivity in both humans and mice. We found that serum stearic acid (SA) is the only fatty acid that is increased dramatically in the postprandial state. The elevation of SA is due to increased insulin-stimulated de novo synthesis mediated by sterol regulatory element–binding protein-1c (SREBP-1c)/acetyl-CoA carboxylase/fatty acid synthase/elongation of long-chain fatty acid family member 6 (ELOVL6) and the elongation of palmitic acid (PA) catalyzed by ELOVL6. Downregulation of SREBP-1c or ELOVL6 by small interfering RNA can reduce SA synthesis in liver and serum SA level, followed by amelioration of IR in HLP mice. However, inhibition of SREBP-1c is more effective in improving IR than suppression of ELOVL6, which resulted in accumulation of PA. In summary, increased postprandial SA is caused by the insulin-stimulated SREBP-1c pathway and elongation of PA in HLP. Reduction of postprandial SA is a good candidate for improving IR, and SREBP-1c is potentially a better target to prevent IR and diabetes by decreasing SA.

Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells

Accumulation of palmitic acid (PA) in cells from nonadipose tissues is known to induce lipotoxicity resulting in cellular dysfunction and death. The exact molecular pathways of PA-induced cell death are still mysterious. Here, we show that PA triggers autophagy, which did not counteract but in contrast promoted endothelial cell death. The PA-induced cell death was predominantly necrotic as indicated by annexin V and propidium iodide (PI) staining, absence of caspase activity, low levels of DNA hypoploidy, and an early ATP depletion. In addition PA induced a strong elevation of mRNA levels of ubiquitin carboxyl-terminal hydrolase (CYLD), a known mediator of necroptosis. Moreover, siRNA-mediated knockdown of CYLD significantly antagonized PA-induced necrosis of endothelial cells. In contrast, inhibition and knockdown of receptor interacting protein kinase 1 (RIPK1) had no effect on PA-induced necrosis, indicating the induction of a CYLD-dependent but RIPK1-independent cell death pathway. PA was recognized as a strong and early inducer of autophagy. The inhibition of autophagy by both pharmacological inhibitors and genetic knockdown of the autophagy-specific genes, vacuolar protein sorting 34 (VPS34), and autophagy-related protein 7 (ATG7), could rescue the PA-induced death of endothelial cells. Moreover, the initiation of autophagy and cell death by PA was reduced in endothelial cells loaded with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-(acetoxymethyl) ester (BAPTA-AM), indicating that Ca(2+) triggers the fatal signaling of PA. In summary, we introduce an unexpected mechanism of lipotoxicity in endothelial cells and provide several novel strategies to counteract the lipotoxic signaling of PA.

Detection and quantification of long chain fatty acids in liquid and solid samples and its relevance to understand anaerobic digestion of lipids

A method for long chain fatty acids (LCFA) extraction, identification and further quantification by gas chromatography was developed and its application to liquid and solid samples collected from anaerobic digesters was demonstrated. After validation, the usefulness of this method was demonstrated in a cow manure digester receiving pulses of an industrial effluent containing high lipid content. From the LCFA analysis data it was showed that the conversion of oleic acid, the main LCFA fed to the reactor, by the adapted biomass became faster and more effective along the successive pulses. Conversely, the accumulation of palmitic acid in the solid phase suggests that degradation of this LCFA, under these conditions, is less effective.

Anaerobic biodegradation of oleic and palmitic acids: Evidence of mass transfer limitations caused by long chain fatty acid accumulation onto the anaerobic sludge

Palmitic acid was the main long chain fatty acids (LCFA) that accumulated onto the anaerobic sludge when oleic acid was fed to an EGSB reactor. The conversion between oleic and palmitic acid was linked to the biological activity. When palmitic acid was fed to an EGSB reactor it represented also the main LCFA that accumulated onto the sludge. The way of palmitic acid accumulation was different in the oleic and in the palmitic acid fed reactors. When oleic acid was fed, the biomass-associated LCFA (83% as palmitic acid) were mainly adsorbed and entrapped in the sludge that became "encapsulated" by an LCFA layer. However, when palmitic acid was fed, the biomass-associated LCFA (the totality as palmitic acid) was mainly precipitated in white spots like precipitates in between the sludge, which remained "non-encapsulated." The two sludges were compared in terms of the specific methanogenic activity (SMA) in the presence of acetate, propionate, butyrate, and H(2)CO(2), before and after the mineralization of similar amounts of biomass-associated LCFA (4.6 and 5.2 g COD-LCFA/g of volatile suspended solids (VSS), for the oleic and palmitic acid fed sludge, respectively). The "non-encapsulated," sludge exhibited a considerable initial methanogenic activity on all the tested substrates, with the single exception of butyrate. However, with the "encapsulated" sludge only methane production from ethanol and H(2)/CO(2) was detected, after a lag phase of about 50 h. After mineralization of the biomass-associated LCFA, both sludges exhibited activities of similar order of magnitude in the presence of the same individual substrates and significantly higher than before. The results evidenced that LCFA accumulation onto the sludge can create a physical barrier and hinder the transfer of substrates and products, inducing a delay on the initial methane production. Whatever the mechanism, metabolic or physical, that is behind this inhibition, it is reversible, being eliminated after the depletion of the biomass-associated LCFA.

Effect of alleles governing 16:0 concentration on glycerolipid composition in developing soybeans

AbstractSoybean [Glycine max (L.) Merr.] oil typically contains 11% palmitic acid, but germplasm with recessive alleles at Fap gene loci exhibit from less than 4% to about 35% 16:0, Although these alleles are used to develop new cultivars, little is known about how they influence palmitic acid concentration. One theory suggests that fap alleles may mediate differences in triacylglycerol composition through genetic effects on the activity or substrate specificity of acyltransferases, such as diacylglycerol acyltransferase (EC 2.3.1.20). Based on logistic function analysis of developing seed, differences in fag allele expression are evident in the rate of palmitic acid accumulation in triacylglycerol, with peak deposition near mid‐seed fill. Acetate saturation kinetics also reveal a strong positive relation between the relative amount of de novo palmitic acid synthesis and the indigenous palmitic acid concentration in triacylglycerol among fap genotypes. However, no differences appear in the kinetics of palmitoyl‐CoA metabolism in developing seed of these genotypes. Therefore, the fap alleles apparently do not encode or regulate the activities of glycerolipid acyltransferase enzymes. Rather, major genetic effects on triacylglycerol composition accrue through regulation of palmitic acid production in the plastids of developing soybean cotyledons.