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International Journal of Molecular... Mar 2021Palmitic acid (PA), a saturated fatty acid enriched in high-fat diet, has been implicated in the development of sarcopenic obesity. Herein, we chose two non-cytotoxic...
Palmitic acid (PA), a saturated fatty acid enriched in high-fat diet, has been implicated in the development of sarcopenic obesity. Herein, we chose two non-cytotoxic concentrations to better understand how excess PA could impact myotube formation or diameter without inducing cell death. Forty-eight hours of 100 µM PA induced a reduction of myotube diameter and increased the number of type I fibers, which was associated with increased miR-206 expression. Next, C2C12 myotube growth in the presence of PA was evaluated. Compared to control cells, 150 µM PA reduces myoblast proliferation and the expression of and miR-206 and miR-133a expression, leading to a reduced number and diameter of myotubes. PA (100 µM), despite not affecting proliferation, impairs myotube formation by reducing the expression of Myf5 and miR-206 and decreasing protein synthesis. Interestingly, 100 and 150 µM PA-treated myotubes had a higher number of type II fibers than control cells. In conclusion, PA affects negatively myotube diameter, fusion, and metabolism, which may be related to myomiRs. By providing new insights into the mechanisms by which PA affects negatively skeletal muscle, our data may help in the discovery of new targets to treat sarcopenic obesity.
Topics: Animals; Cell Line; Gene Expression Regulation; Mice; MicroRNAs; Muscle Development; Myoblasts, Skeletal; Palmitic Acid
PubMed: 33803124
DOI: 10.3390/ijms22052748 -
The Journal of Physiology Sep 2023Well-regulated placental palmitic acid (PA) and oleic acid (OA) metabolism is vital for optimal placental function and fetal development, but dysregulation occurs with...
Well-regulated placental palmitic acid (PA) and oleic acid (OA) metabolism is vital for optimal placental function and fetal development, but dysregulation occurs with gestational diabetes (GDM). We hypothesized that such dysregulation might arise from increased maternofetal glucose, leptin or insulin concentrations present in GDM, and that dysregulated PA and OA lipid metabolism could be moderated by myo-inositol, a natural polyol and potential GDM intervention. Placental explants from 21 women were incubated with stable isotope-labelled C-PA or C-OA for 48 h. Explants were treated with glucose (5, 10 mm) or leptin (13 nm) or insulin (150 nm) in combination with myo-inositol (0.3, 30, 60 μm). Forty-seven C-PA lipids and 37 C-OA lipids were measured by liquid chromatography-mass spectrometry (LCMS). Compared with controls (5 mm glucose), glucose (10 mm) increased 19 C-OA lipids and nine C-PA lipids, but decreased C-OA phosphatidylethanolamine 38:5 and C-PA phosphatidylethanolamine 36:4. The effects of leptin and insulin were less prominent than glucose, with leptin increasing C-OA acylcarnitine 18:1, and insulin increasing four C-PA triacylglycerides. Most glucose, leptin and insulin-induced alterations in lipids were attenuated by co-incubation with myo-inositol (30 or 60 μm), with attenuation also occurring in all subgroups stratified by GDM status and fetal sex. However, glucose-induced increases in acylcarnitine were not attenuated by myo-inositol and were even exaggerated in some instances. Myo-inositol therefore appears to generally act as a moderator, suppressing the perturbation of lipid metabolic processes by glucose, leptin and insulin in placenta in vitro. Whether myo-inositol protects the fetus and pregnancy from unfavourable outcomes requires further research. KEY POINTS: Incubation of placental explants with additional glucose, or to a lesser extent insulin or leptin, alters the placental production of C-lipids from C-palmitic acid (PA) and C-oleic acid (OA) in vitro compared with untreated controls from the same placenta. Co-incubation with myo-inositol attenuated most alterations induced by glucose, insulin or leptin in C-lipids, but did not affect alterations in C-acylcarnitines. Alterations induced by glucose and leptin in C-PA triacylglycerides and C-PA phospholipids were influenced by fetal sex and gestational diabetes status, but were all still attenuated by myo-inositol co-incubation. Insulin differently affected C-PA triacylglycerides and C-PA phospholipids depending on fetal sex, with alterations also attenuated by myo-inositol co-incubation.
Topics: Pregnancy; Female; Humans; Insulin; Oleic Acid; Palmitic Acid; Phosphatidylethanolamines; Leptin; Diabetes, Gestational; Placenta; Glucose
PubMed: 37602663
DOI: 10.1113/JP285036 -
International Journal of Molecular... Mar 2023Sarcopenia associated with aging and obesity is characterized by the atrophy of fast-twitch muscle fibers and an increase in intramuscular fat deposits. However, the...
Sarcopenia associated with aging and obesity is characterized by the atrophy of fast-twitch muscle fibers and an increase in intramuscular fat deposits. However, the mechanism of fast-twitch fiber-specific atrophy remains unclear. In this study, we aimed to assess the effect of palmitic acid (PA), the most common fatty acid component of human fat, on muscle fiber type, focusing on the expression of fiber-type-specific myosin heavy chain (MHC). Myotubes differentiated from C2C12 myoblasts were treated with PA. The PA treatment inhibited myotube formation and hypertrophy while reducing the gene expression of MHC IIb and IIx, specific isoforms of fast-twitch fibers. Consistent with this, a significant suppression of MHC IIb protein expression in PA-treated cells was observed. A reporter assay using plasmids containing the MHC IIb gene promoter revealed that the PA-induced reduction in MHC IIb gene expression was caused by the suppression of MyoD transcriptional activity through its phosphorylation. Treatment with a specific protein kinase C (PKC) inhibitor recovered the reduction in MHC IIb gene expression levels in PA-treated cells, suggesting the involvement of the PA-induced activation of PKC. Thus, PA selectively suppresses the mRNA and protein expression of fast-twitch MHC by modulating MyoD activity. This finding provides a potential pathogenic mechanism for age-related sarcopenia.
Topics: Humans; Muscle Fibers, Skeletal; Muscle, Skeletal; Myosin Heavy Chains; Palmitic Acid; Phosphorylation; Sarcopenia; Animals; Mice; MyoD Protein
PubMed: 36982919
DOI: 10.3390/ijms24065847 -
Nutrients Aug 2023Metabolic endotoxemia (ME) is characterized by a 2-3-fold increase in blood endotoxin levels and low-grade systemic inflammation without apparent infection. ME is...
Metabolic endotoxemia (ME) is characterized by a 2-3-fold increase in blood endotoxin levels and low-grade systemic inflammation without apparent infection. ME is usually accompanied by metabolic syndrome, characterized by central obesity and hyperlipidemia. According to numerous studies, ME may lead to functional brain disorders, including cognitive decline, depression, and dementia. In the current in vitro study, we aimed to determine the direct and indirect impact of endotoxin (LPS) and palmitic acid (PA), representing saturated fatty acids, on the inflammatory and oxidative stress response in the human microglial HMC3 cells unstimulated and stimulated with IFNγ. The study's results revealed that direct HMC3 cell exposition to endotoxin and PA increased inflammatory response measured as levels of IL-6 and MCP-1 released into the medium and PGE2 levels in cell lysates. Moreover, direct HMC3 cell treatment with PA and LPS induced oxidative stress, i.e., ROS and COX-2 production and lipid peroxidation. On the contrary, an indirect effect of LPS and PA on microglial cells, assessed as the impact of macrophage metabolites, was much lower regarding the inflammatory response, although still associated with oxidative stress. Interestingly, IFNγ had a protective effect on microglial cells, reducing the production of pro-inflammatory mediators and oxidative stress in HMC3 cells treated directly and indirectly with LPS and PA.
Topics: Humans; Microglia; Palmitic Acid; Endotoxemia; Lipopolysaccharides; Inflammation
PubMed: 37571401
DOI: 10.3390/nu15153463 -
International Journal of Molecular... Sep 2023Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids within hepatocytes, which compromises liver functionality following...
Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids within hepatocytes, which compromises liver functionality following mitochondrial dysfunction and increased production of reactive oxygen species (ROS). Lipoic acid is one of the prosthetic groups of the pyruvate dehydrogenase complex also known for its ability to confer protection from oxidative damage because of its antioxidant properties. In this study, we aimed to investigate the effects of lipoic acid on lipotoxicity and mitochondrial dynamics in an in vitro model of liver steatosis. HepG2 cells were treated with palmitic acid and oleic acid (1:2) to induce steatosis, without and with 1 and 5 µM lipoic acid. Following treatments, cell proliferation and lipid droplets accumulation were evaluated. Mitochondrial functions were assessed through the evaluation of membrane potential, MitoTracker Red staining, expression of genes of the mitochondrial quality control, and analysis of energy metabolism by HPLC and Seahorse. We showed that lipoic acid treatment restored membrane potential to values comparable to control cells, as well as protected cells from mitochondrial fragmentation following PA:OA treatment. Furthermore, our data showed that lipoic acid was able to determine an increase in the expression of mitochondrial fusion genes and a decrease in mitochondrial fission genes, as well as to restore the bioenergetics of cells after treatment with palmitic acid and oleic acid. In conclusion, our data suggest that lipoic acid reduces lipotoxicity and improves mitochondrial functions in an in vitro model of steatosis, thus providing a potentially valuable pharmacological tool for NAFLD treatment.
Topics: Humans; Thioctic Acid; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Oleic Acid; Mitochondria; Hepatocytes; Oxidative Stress; Energy Metabolism; Liver
PubMed: 37833939
DOI: 10.3390/ijms241914491 -
Cellular and Molecular Life Sciences :... Jul 2019Emerging evidence shows that palmitic acid (PA), a common fatty acid in the human diet, serves as a signaling molecule regulating the progression and development of many... (Review)
Review
Emerging evidence shows that palmitic acid (PA), a common fatty acid in the human diet, serves as a signaling molecule regulating the progression and development of many diseases at the molecular level. In this review, we focus on its regulatory roles in the development of five pathological conditions, namely, metabolic syndrome, cardiovascular diseases, cancer, neurodegenerative diseases, and inflammation. We summarize the clinical and epidemiological studies; and also the mechanistic studies which have identified the molecular targets for PA in these pathological conditions. Activation or inactivation of these molecular targets by PA controls disease development. Therefore, identifying the specific targets and signaling pathways that are regulated by PA can give us a better understanding of how these diseases develop for the design of effective targeted therapeutics.
Topics: Animals; Autophagy; Cardiovascular Diseases; Humans; Inflammation; Metabolic Syndrome; Neoplasms; Neurodegenerative Diseases; Palmitic Acid; Signal Transduction
PubMed: 30968170
DOI: 10.1007/s00018-019-03092-7 -
International Journal of Molecular... Oct 2023Neuroblastoma (NB) is a childhood cancer, commonly treated with drugs, such as etoposide (ETO), whose efficacy is limited by the onset of resistance. Here, aiming at...
Imidazo-Pyrazole-Loaded Palmitic Acid and Polystyrene-Based Nanoparticles: Synthesis, Characterization and Antiproliferative Activity on Chemo-Resistant Human Neuroblastoma Cells.
Neuroblastoma (NB) is a childhood cancer, commonly treated with drugs, such as etoposide (ETO), whose efficacy is limited by the onset of resistance. Here, aiming at identifying new treatments for chemo-resistant NB, the effects of two synthesized imidazo-pyrazoles (IMPs) ( and ) were investigated on ETO-sensitive (HTLA-230) and ETO-resistant (HTLA-ER) NB cells, detecting as the more promising compound, that demonstrated IC values lower than those of ETO on HTLA ER. Therefore, to further improve the activity of , we developed -loaded palmitic acid (PA) and polystyrene-based (P5) cationic nanoparticles (P5PA-4I NPs) with high drug loading (21%) and encapsulation efficiency (97%), by a single oil-in-water emulsification technique. Biocompatible PA was adopted as an emulsion stabilizer, while synthesized P5 acted as an encapsulating agent, solubilizer and hydrophilic-lipophilic balance (HLB) improver. Optic microscopy and cytofluorimetric analyses were performed to investigate the micromorphology, size and complexity distributions of P5PA-4I NPs, which were also structurally characterized by chemometric-assisted Fourier transform infrared spectroscopy (FTIR). Potentiometric titrations allowed us to estimate the milliequivalents of PA and basic nitrogen atoms present in NPs. P5PA-4I NPs afforded dispersions in water with excellent buffer capacity, essential to escape lysosomal degradation and promote long residence time inside cells. They were chemically stable in an aqueous medium for at least 40 days, while in dynamic light scattering (DLS) analyses, P5PA-4I showed a mean hydrodynamic diameter of 541 nm, small polydispersity (0.194), and low positive zeta potentials (+8.39 mV), assuring low haemolytic toxicity. Biological experiments on NB cells, demonstrated that P5PA-4I NPs induced ROS-dependent cytotoxic effects significantly higher than those of pristine , showing a major efficacy compared to ETO in reducing cell viability in HTLA-ER cells. Collectively, this -based nano-formulation could represent a new promising macromolecular platform to develop a new delivery system able to increase the cytotoxicity of the anticancer drugs.
Topics: Humans; Child; Drug Carriers; Palmitic Acid; Polystyrenes; Etoposide; Antineoplastic Agents; Neuroblastoma; Nanoparticles; Water
PubMed: 37834475
DOI: 10.3390/ijms241915027 -
Nutrition Research Reviews Jun 2009The position of fatty acids in the TAG molecule (sn-1, sn-2 and sn-3) determines the physical properties of the fat, which affects its absorption, metabolism and... (Review)
Review
The position of fatty acids in the TAG molecule (sn-1, sn-2 and sn-3) determines the physical properties of the fat, which affects its absorption, metabolism and distribution into tissues, which may have implications for the risk of CHD. The TAG structure of fats can be manipulated by the process of interesterification, which is of increasing commercial importance, as it can be used to change the physical characteristics of a fat without the generation of trans-fatty acids. Interesterified fats rich in long-chain SFA are commercially important, but few studies have investigated their health effects. Evidence from animal and human infant studies suggests that TAG structure and interesterification affect digestibility, atherogenicity and fasting lipid levels, with fats containing palmitic and stearic acid in the sn-2 position being better digested and considered to be more atherogenic. However, chronic studies in human adults suggest that TAG structure has no effect on digestibility or fasting lipids. The postprandial effects of fats with differing TAG structure are better characterised but the evidence is inconclusive; it is probable that differences in the physical characteristics of fats resulting from interesterification and changes in TAG structure are key determinants of the level of postprandial lipaemia, rather than the position of fatty acids in the TAG. The present review gives an overview of TAG structure and interesterified palmitic and stearic acid-rich fats, their physical properties and their acute and chronic effects in human adults in relation to CHD.
Topics: Adult; Animals; Coronary Disease; Diet, Atherogenic; Dietary Fats; Esterification; Humans; Hyperlipidemias; Infant; Lipid Metabolism; Lipids; Palmitic Acid; Plant Oils; Stearic Acids; Trans Fatty Acids; Triglycerides
PubMed: 19442321
DOI: 10.1017/S0954422409369267 -
The American Journal of Clinical... May 2021Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism. (Randomized Controlled Trial)
Randomized Controlled Trial
Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared with a MUFA-rich oil: A randomized controlled trial.
BACKGROUND
Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism.
OBJECTIVES
To test the impact of a commonly consumed IE compared with a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil [rapeseed oil (RO)].
METHODS
A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n = 20) aged 45-75 y. Postprandial plasma triacylglycerol and lipoprotein responses (including stable isotope tracing) to a test meal (50 g fat) were evaluated over 8 h. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM).
RESULTS
Plasma triacylglycerol 8-h incremental area under the curves were lower following non-IE compared with RO [-1.7 mmol/L⋅h (95% CI: -3.3, -0.0)], but there were no differences between IE and RO or IE and non-IE. LDL particles were smaller following IE and non-IE compared with RO (P = 0.005). Extra extra large, extra large, and large VLDL particle concentrations were higher following IE and non-IE compared with RO at 6-8 h (P < 0.05). No differences in the appearance of [13C]palmitic acid in plasma triacylglycerol were observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of SFAs compared with RO.
CONCLUSIONS
Interesterification did not modify fat digestion, postprandial lipemia, or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA-rich fats, increased proatherogenic large triacylglycerol-rich lipoprotein remnant and small LDL particles following the SFA-rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFAs to cardiovascular disease risk.
Topics: Aged; Apolipoprotein B-48; Atherosclerosis; Chylomicrons; Cross-Over Studies; Dietary Fats, Unsaturated; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Humans; Hyperlipidemias; Lipoproteins; Male; Middle Aged; Palmitic Acid; Postprandial Period; Triglycerides
PubMed: 33675343
DOI: 10.1093/ajcn/nqaa413 -
Neural Plasticity 2018The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these... (Review)
Review
The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation) within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LICs). From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior.
Topics: Animals; Humans; Ion Channels; Lipoylation; Neurons; Palmitic Acid; Receptors, G-Protein-Coupled; Receptors, Neurotransmitter
PubMed: 29849559
DOI: 10.1155/2018/5701348