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European Journal of Immunology Jun 2024Unsaturated fatty acids (UFA) are crucial for T-cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless,...
Unsaturated fatty acids (UFA) are crucial for T-cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless, the mechanisms by which UFA affects T-cell behavior are ill-defined. Therefore, we analyzed the processing of oleic acid, a prominent UFA abundantly present in blood, adipocytes, and the fat pads surrounding lymph nodes, in CD4 T cells. We found that exogenous oleic acid increases proliferation and enhances the calcium flux response upon CD3/CD28 activation. By using a variety of techniques, we found that the incorporation of oleic acid into membrane lipids, rather than regulation of cellular metabolism or TCR expression, is essential for its effects on CD4 T cells. These results provide novel insights into the mechanism through which exogenous oleic acid enhances CD4 T-cell function.
PubMed: 38890809
DOI: 10.1002/eji.202350685 -
Journal of Neuroscience Research May 2024Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also...
Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid β-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.
Topics: Animals; Astrocytes; Oleic Acid; Female; Palmitic Acid; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Sex Characteristics; Cells, Cultured
PubMed: 38741550
DOI: 10.1002/jnr.25339 -
Advances in Pharmacological and... 2024Nutritional supplements are gaining traction for their effects in mitigating the impacts of various health conditions. In particular, many supplements are being proposed...
Nutritional supplements are gaining traction for their effects in mitigating the impacts of various health conditions. In particular, many supplements are being proposed to reduce the impacts of type 2 diabetes (T2D), a metabolic condition that has reached global epidemic proportions. Recently, a supplement of oleic acid (OA) and succinic acid (SA; 1 : 1, w/w) was reported to improve glycaemic control in type 2 diabetic (T2D) Sprague-Dawley (S-D) rats through ameliorating insulin release and sensitivity. Here, we investigate the effects of the supplement (OA and SA) on hepatic and pancreatic function in T2D S-D rats. Eighteen (18) S-D rats were rendered diabetic and were divided into three equal groups: diabetic control, diabetic treatment, and diabetic glibenclamide. Another 12 S-D rats were obtained and served as the normal groups. The animals were treated daily with the vehicle, OA and SA (800 mg/kg body weight (bw); 1 : 1), or glibenclamide (10 mg/kg bw) which served as the positive control. The findings indicated that treatment with the supplement resulted in a 35.69 ± 4.22% reduction (=0.006) in blood glucose levels (BGL). Analysis of hepatic enzymes depicted that the nutritional supplement reduced the activity of the gluconeogenesis enzyme, glucose-6-phosphatase (G6P) while improved the activity of catabolic enzymes such as glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK). Furthermore, the supplement attenuated oxidative stress through restoration of catalase (CAT) and superoxide dismutase (SOD), while reducing malondialdehyde (MDA) levels. Finally, the supplement showed no liver or kidney toxicity and improved the size and number of pancreatic islets of Langerhans, indicating its potential application in treating T2D. The study highlighted that a supplement of the two organic acids may be beneficial in reducing the rate of pathogenesis of type 2 diabetes. Therefore, it may offer therapeutic value as a dietary or nutritional supplement in the approach against diabetes and its complications.
PubMed: 38938594
DOI: 10.1155/2024/5556722 -
Frontiers in Pharmacology 2023Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120....
Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120. Pretreatment with GPR40 agonists enhanced the secretion of insulin in response to elevating blood glucose levels after glucose load in a diabetes model, but pretreatment with GPR120 agonist did not ameliorate postprandial hyperglycemia. This study examined whether oral administration of linoleic acid (LA), a GPR40 and GPR120 agonist, immediately before glucose load would affect the elevation of postprandial blood glucose levels in rats. Male rats and rats with type 1 diabetes administered streptozocin were orally administered LA, trilinolein, α-linolenic acid (α-LA), oleic acid, TAK-875, or TUG-891 immediately before glucose load. Blood glucose levels were measured before, then 15, 30, 60 and 120 min after glucose load. CACO-2 cells were used to measure the uptake of [C] α-MDG for 30 min with or without LA. Gastric content from rats administered LA was collected 15 and 30 min after glucose load, and blood samples were collected for measurement of glucagon-like peptide 1 (GLP-1) and cholecystokinin concentrations. The elevation of postprandial blood glucose levels was slowed by LA but not by trilinolein in rats without promotion of insulin secretion, and this effect was also observed in rats with type 1 diabetes. The uptake of α-MDG, an SGLT-specific substrate, was, however, not inhibited by LA. Gastric emptying was slowed by LA 15 min after glucose load, and GLP-1, but not cholecystokinin, level was elevated by LA 15 min after glucose load. TUG-891, a GPR120 agonist, ameliorated postprandial hyperglycemia but TAK-875, a GPR40 agonist, did not. Pretreatment with AH7614, a GPR120 antagonist, partially canceled the improvement of postprandial hyperglycemia induced by LA. α-LA, which has high affinity with GPR120 as well as LA, slowed the elevation of postprandial blood glucose levels, but oleic acid, which has lower affinity with GPR120 than LA, did not. Oral administration of LA immediately after glucose load ameliorated postprandial hyperglycemia due to slowing of gastric emptying via promotion of GLP-1 secretion. The mechanisms may be associated with GPR120 pathway.
PubMed: 37583904
DOI: 10.3389/fphar.2023.1197743 -
Journal of Translational Medicine Jan 2024Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play significant roles in NAFLD pathogenesis. The unfolded protein response in mitochondria (UPRmt) is an adaptive mechanism that aims to restore mitochondrial protein homeostasis and mitigate cellular stress. This study aimed to investigate the effects of ( +)-Lipoic acid (ALA) on UPRmt, inflammation, and oxidative stress in an in vitro model of NAFLD using HepG2 cells treated with palmitic acid and oleic acid to induce steatosis.
RESULTS
Treatment with palmitic and oleic acids increased UPRmt-related proteins HSP90 and HSP60 (heat shock protein), and decreased CLPP (caseinolytic protease P), indicating ER stress activation. ALA treatment at 1 μM and 5 μM restored UPRmt-related protein levels. PA:OA (palmitic acid:oleic acid)-induced ER stress markers IRE1α (Inositol requiring enzyme-1), CHOP (C/EBP Homologous Protein), BIP (Binding Immunoglobulin Protein), and BAX (Bcl-2-associated X protein) were significantly reduced by ALA treatment. ALA also enhanced ER-mediated protein glycosylation and reduced oxidative stress, as evidenced by decreased GPX1 (Glutathione peroxidase 1), GSTP1 (glutathione S-transferase pi 1), and GSR (glutathione-disulfide reductase) expression and increased GSH (Glutathione) levels, and improved cellular senescence as shown by the markers β-galactosidase, γH2Ax and Klotho-beta.
CONCLUSIONS
In conclusion, ALA ameliorated ER stress, oxidative stress, and inflammation in HepG2 cells treated with palmitic and oleic acids, potentially offering therapeutic benefits for NAFLD providing a possible biochemical mechanism underlying ALA beneficial effects.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Thioctic Acid; Endoribonucleases; Oleic Acid; Protein Serine-Threonine Kinases; Unfolded Protein Response; Oxidative Stress; Endoplasmic Reticulum Stress; Hepatocytes; Cellular Senescence; Inflammation; Palmitic Acids; Liver; Palmitic Acid
PubMed: 38245790
DOI: 10.1186/s12967-024-04880-x -
ACS Omega Feb 2024A novel combination of antibiotic, ciprofloxacin (CIP) with herbal counterpart naringin (NAR) was encapsulated by an oleic acid lipid core and carboxymethyl chitosan...
Co-Delivery of Naringin and Ciprofloxacin by Oleic Acid Lipid Core Encapsulated in Carboxymethyl Chitosan/Alginate Nanoparticle Composite for Enhanced Antimicrobial Activity.
A novel combination of antibiotic, ciprofloxacin (CIP) with herbal counterpart naringin (NAR) was encapsulated by an oleic acid lipid core and carboxymethyl chitosan (CM-CS)/Alginate (AG) nanoparticle composite (CIP + NAR-CM-CS/AG-NPs) for improved antimicrobial efficacy of antibiotic. Herein, this study explored the design and preparation of a composite system that enables to deliver both CIP and NAR from the oleic acid lipid core of CM-CS/AG nanoparticles using a nonsolvent ionic gelation technique. The nanoparticles (NPs) were fabricated with improved long-acting antimicrobial activity against and . The optimized composition was investigated for physicochemical properties particle size, particle distribution, and ζ-potential. A diverse array of analytical tools was employed to characterize the optimized formulation including DSC, XRD, Malvern Zetasizer for particle size, ζ-potential, TEM, and SEM. Further, the preparation was investigated for % drug release, flux determination, antioxidant, and antimicrobial activity. The formulation stability was tested for 90 days and also evaluated formulation stability in fetal bovine serum to inspect the modification in physicochemical characteristics. NPs size was determined at 85 nm, PDI, and ζ-potential was recorded at 0.318, and 0.7 ± 0.4 mV. The % CIP and NAR entrapment efficiency and % loading were incurred as 91 ± 1.9, and 89.5 ± 1.2; 11.5 ± 0.6, and 10.8 ± 0.5%, respectively. The drug release erupted in the beginning phase followed by sustained and prolonged release for 48 h. The analytical experiments by DSC ensured the noninteracting and safe use of excipients in combination. X-ray studies demonstrated the amorphous state of the drug in the formulation. The insignificant alteration of formulation characteristics in FBS suggested stable and robust preparation. Storage stability of the developed formulation ensured consistent and uniform stability for three months. The DPPH assays demonstrated that NAR had good antioxidant capacity and supported improving antimicrobial activity of CIP. The hemolytic test suggested the developed formulation was compatible and caused insignificant RBC destruction. The in-house built formulation CIP + NAR-CM-CS/AG-NPs significantly improved the antimicrobial activity compared to CIP alone, offering a novel choice in antimicrobial application.
PubMed: 38371782
DOI: 10.1021/acsomega.3c08200 -
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 -
Frontiers in Endocrinology 2023
Topics: Endocannabinoids
PubMed: 38027133
DOI: 10.3389/fendo.2023.1263924 -
Metabolism: Clinical and Experimental Aug 2023Na/K-ATPase (NKA), an ion pumping enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However,...
BACKGROUND
Na/K-ATPase (NKA), an ion pumping enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However, the role of NKA in hepatic lipid homeostasis has yet to be fully characterized.
METHODS
The activity of NKA and NKAα1 expression were determined in steatotic cells, mice and patients. The roles of NKAα1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKAα1 in mice.
RESULTS
Herein, we demonstrated that the expression and activity of α1 subunit of NKA (NKAα1) were lowered in the livers of nonalcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-induced obese mice, and genetically obese (ob/ob, db/db) mice, as well as oleic acid-induced hepatocytes. Hepatic deficiency of NKAα1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKAα1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKAα1 upregulated sirtuin 1 (SIRT1) via interacting with ubiquitin specific peptidase 22 (USP22), a deubiquitinating enzyme for the stabilization and deubiquitination of SIRT1, thus activating the downstream autophagy signaling. Blockade of the SIRT1/autophagy signaling pathway eliminated the protective effects of NKAα1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (DVEDSYGQQWTYEQR) of NKAα1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKAα1 and inducing its activation.
CONCLUSIONS
Collectively, this study renews the functions of NKAα1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKAα1.
Topics: Mice; Animals; Mice, Obese; Lipid Metabolism; Sirtuin 1; Liver; Non-alcoholic Fatty Liver Disease; Hepatocytes; Oleic Acid; Diet, High-Fat; Mice, Inbred C57BL
PubMed: 37127227
DOI: 10.1016/j.metabol.2023.155579 -
Scientific Reports Oct 2023To investigate the effects and potential mechanisms of human umbilical cord mesenchymal stem cells, exosomes, and their conditioned media on lipid storage in oleic acid...
To investigate the effects and potential mechanisms of human umbilical cord mesenchymal stem cells, exosomes, and their conditioned media on lipid storage in oleic acid (OA) and palmitic acid (PA) treated hepatocytes and high-fat methionine- choline deficient diet (HFMRCD) induced non-alcoholic steatohepatitis (NASH) mice. AML12 cells were stimulated with OA and PA to establish the lipid storage cell model. HucMSCs, exosomes, and culture medium were then co-cultured. At the same time, C57BL/6 mice were fed an HFMRCD for 6 or 8 weeks to establish a NASH mouse model. The effect of HucMSCs, exosomes, and culture medium on lipid droplet repair of hepatocytes or NASH mice was then assessed. The weight of hepatocytes or liver tissue, Oil Red O, hematoxylin-eosin staining, Masson staining, Western blot, and qPCR were used to detect the related IL-6, TNF-α, TGF-β1 andEI24/AMPK/mTOR pathway expression in hepatocytes and liver tissue. Compared with the model group, the effect of HucMSCs-Ex on inhibiting the accumulation of lipid droplets was more obvious at the cell level. In vivo study showed that HucMSCs-Ex reduces activity scores in NASH mice and improves liver tissue morphology by reducing vacuolar degeneration, fat deposition, and collagen deposition of liver tissue. Western blot and qPCR results showed that inflammatory factors and AMPK/mTOR or EI24-related autophagy pathways were altered before and after treatment. HucMSCs, HucMSC-Ex, and CM can promote autophagy in hepatocytes or NASH mice through the AMPK/mTOR or EI24-related autophagy pathway and alleviate injury associated with lipid deposition, collagen deposition or inflammation, reversing the progression of NASH.
Topics: Mice; Humans; Animals; Non-alcoholic Fatty Liver Disease; Culture Media, Conditioned; Exosomes; AMP-Activated Protein Kinases; Mice, Inbred C57BL; Liver; TOR Serine-Threonine Kinases; Palmitic Acid; Choline; Oleic Acid; Collagen; Mesenchymal Stem Cells
PubMed: 37891247
DOI: 10.1038/s41598-023-45828-3