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Redox Biology Sep 2020Macrophages play a pivotal role in the early stages of atherosclerosis development; they excessively accumulate cholesterol in the cytosol in response to modified Low...
Macrophages play a pivotal role in the early stages of atherosclerosis development; they excessively accumulate cholesterol in the cytosol in response to modified Low Density Lipoprotein (mLDL). The mLDL are incorporated through scavenger receptors. CD36 is a high-affinity cell surface scavenger receptor that facilitates the binding and uptake of long-chain fatty acids and mLDL into the cell. Numerous structurally diverse ligands can initiate signaling responses through CD36 to regulate cell metabolism, migration, and angiogenesis. Nitro-fatty acids are endogenous electrophilic lipid mediators that react with and modulate the function of multiple enzymes and transcriptional regulatory proteins. These actions induce the expression of several anti-inflammatory and cytoprotective genes and limit pathologic responses in experimental models of atherosclerosis, cardiac ischemia/reperfusion, and inflammatory diseases. Pharmacological and genetic approaches were used to explore the actions of nitro-oleic acid (NO-OA) on macrophage lipid metabolism. Pure synthetic NO-OA dose-dependently increased CD36 expression in RAW264.7 macrophages and this up-regulation was abrogated in BMDM from Nrf2-KO mice. Ligand binding analysis revealed that NO-OA specifically interacts with CD36, thus limiting the binding and uptake of mLDL. Docking analysis shows that NO-OA establishes a low binding energy interaction with the alpha helix containing Lys164 in CD36. NO-OA also restored autophagy flux in mLDL-loaded macrophages, thus reversing cholesterol deposition within the cell. In aggregate, these results indicate that NO-OA reduces cholesterol uptake by binding to CD36 and increases cholesterol efflux by restoring autophagy.
Topics: Animals; CD36 Antigens; Cholesterol; Foam Cells; Ligands; Lipoproteins, LDL; Macrophages; Mice; Oleic Acid
PubMed: 32531545
DOI: 10.1016/j.redox.2020.101591 -
Journal of Hematology & Oncology Jun 2022Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however,...
Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however, the effect of mammary adipocytes on breast cancer ferroptosis remains to be elucidated. Here, we established the co-culture system of adipocyte-breast cancer cells and revealed the protection of triple-negative breast cancer from ferroptosis by adipocytes. Then, we performed the lipidomics analysis comparing lipid metabolites of co-cultured and normal-cultured cells. Mechanistically, oleic acid secreted from adipocytes inhibited lipid peroxidation and ferroptosis of triple-negative breast cancer cells in the presence of ACSL3. Taken together, mammary adipocytes can protect breast cancer cells from ferroptosis through oleic acid in the presence of ACSL3. These findings could provide new ideas and targets for tumor treatment.
Topics: Adipocytes; Ferroptosis; Humans; Lipid Peroxidation; Oleic Acid; Triple Negative Breast Neoplasms
PubMed: 35659320
DOI: 10.1186/s13045-022-01297-1 -
Genomics, Proteomics & Bioinformatics Oct 2021Oleic acid (OA), a monounsaturated fatty acid (MUFA), has previously been shown to reverse saturated fatty acid palmitic acid (PA)-induced hepatic insulin resistance...
Oleic acid (OA), a monounsaturated fatty acid (MUFA), has previously been shown to reverse saturated fatty acid palmitic acid (PA)-induced hepatic insulin resistance (IR). However, its underlying molecular mechanism is unclear. In addition, previous studies have shown that eicosapentaenoic acid (EPA), a ω-3 polyunsaturated fatty acid (PUFA), reverses PA-induced muscle IR, but whether EPA plays the same role in hepatic IR and its possible mechanism involved need to be further clarified. Here, we confirmed that EPA reversed PA-induced IR in HepG2 cells and compared the proteomic changes in HepG2 cells after treatment with different free fatty acids (FFAs). A total of 234 proteins were determined to be differentially expressed after PA+OA treatment. Their functions were mainly related to responses to stress and endogenous stimuli, lipid metabolic process, and protein binding. For PA+EPA treatment, the PA-induced expression changes of 1326 proteins could be reversed by EPA, 415 of which were mitochondrial proteins, with most of the functional proteins involved in oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Mechanistic studies revealed that the protein encoded by JUN and reactive oxygen species (ROS) play a role in OA- and EPA-reversed PA-induced IR, respectively. EPA and OA alleviated PA-induced abnormal adenosine triphosphate (ATP) production, ROS generation, and calcium (Ca) content. Importantly, HO-activated production of ROS increased the protein expression of JUN, further resulting in IR in HepG2 cells. Taken together, we demonstrate that ROS/JUN is a common response pathway employed by HepG2 cells toward FFA-regulated IR.
Topics: Eicosapentaenoic Acid; Hep G2 Cells; Humans; Hydrogen Peroxide; Insulin Resistance; Oleic Acid; Palmitic Acid; Proteomics; Reactive Oxygen Species
PubMed: 33631425
DOI: 10.1016/j.gpb.2019.06.005 -
International Journal of Molecular... Aug 2021Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases which lacks ideal treatment options. Kaempferol and kaempferide, two natural flavonol...
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases which lacks ideal treatment options. Kaempferol and kaempferide, two natural flavonol compounds isolated from L., were reported to exhibit a strong regulatory effect on lipid metabolism, for which the mechanism is largely unknown. In the present study, we investigated the effects of kaempferol and kaempferide on oleic acid (OA)-treated HepG2 cells, a widely used in vitro model of NAFLD. The results indicated an increased accumulation of lipid droplets and triacylglycerol (TG) by OA, which was attenuated by kaempferol and kaempferide (5, 10 and 20 μM). Western blot analysis demonstrated that kaempferol and kaempferide reduced expression of lipogenesis-related proteins, including sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1). Expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer binding proteins β (C/EBPβ), two adipogenic transcription factors, was also decreased by kaempferol and kaempferide treatment. In addition, western blot analysis also demonstrated that kaempferol and kaempferide reduced expression of heme oxygenase-1 (HO-1) and nuclear transcription factor-erythroid 2-related factor 2 (Nrf2). Molecular docking was performed to identify the direct molecular targets of kaempferol and kaempferide, and their binding to SCD-1, a critical regulator in lipid metabolism, was revealed. Taken together, our findings demonstrate that kaempferol and kaempferide could attenuate OA-induced lipid accumulation and oxidative stress in HepG2 cells, which might benefit the treatment of NAFLD.
Topics: Carcinoma, Hepatocellular; Fatty Liver; Hep G2 Cells; Humans; Kaempferols; Lipogenesis; Liver Neoplasms; Oleic Acid; Oxidative Stress; Signal Transduction
PubMed: 34445549
DOI: 10.3390/ijms22168847 -
Nutrients Aug 2019Olive oil is one of the main ingredients in the Mediterranean diet, being an important ally in disease prevention. Its nutritional composition is comprised of mainly... (Review)
Review
Olive oil is one of the main ingredients in the Mediterranean diet, being an important ally in disease prevention. Its nutritional composition is comprised of mainly monounsaturated fatty acids, with oleic being the major acid, plus minor components which act as effective antioxidants, such as hydroxytyrosol. Studies have shown that the consumption of olive oil, as well as its isolated components or in synergism, can be a primary and secondary protective factor against the development of cardiovascular diseases since it reduces the concentrations of low-density lipoproteins and increases the concentration of high-density lipoproteins. Furthermore, it exerts an influence on the inflammatory markers, such as interleukin-6 and tumor necrosis factor, which are pro-inflammatory agents in the body. The components present in olive oil are also associated with the promotion of intestinal health since they stimulate a higher biodiversity of beneficial gut bacteria, enhancing their balance. The objective of this review is to present recent data on investigated effects of olive oil and its components on the metabolism, focused on cardiovascular diseases, inflammation, and gut biota.
Topics: Adult; Biomarkers; Cardiovascular Diseases; Diet, Mediterranean; Gastrointestinal Microbiome; Humans; Inflammation; Lipoproteins, LDL; Oleic Acid; Olive Oil; Phenols; Phenylethyl Alcohol
PubMed: 31394805
DOI: 10.3390/nu11081826 -
Biomolecules Aug 2020α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4-5), Ca-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the... (Review)
Review
α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4-5), Ca-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the lactating mammary gland. The protein possesses a single strong Ca-binding site, which can also bind Mg, Mn, Na, K, and some other metal cations. It contains several distinct Zn-binding sites. Physical properties of α-LA strongly depend on the occupation of its metal binding sites by metal ions. In the absence of bound metal ions, α-LA is in the molten globule-like state. The binding of metal ions, and especially of Ca, increases stability of α-LA against the action of heat, various denaturing agents and proteases, while the binding of Zn to the Ca-loaded protein decreases its stability and causes its aggregation. At pH 2, the protein is in the classical molten globule state. α-LA can associate with membranes at neutral or slightly acidic pH at physiological temperatures. Depending on external conditions, α-LA can form amyloid fibrils, amorphous aggregates, nanoparticles, and nanotubes. Some of these aggregated states of α-LA can be used in practical applications such as drug delivery to tissues and organs. α-LA and some of its fragments possess bactericidal and antiviral activities. Complexes of partially unfolded α-LA with oleic acid are cytotoxic to various tumor and bacterial cells. α-LA in the cytotoxic complexes plays a role of a delivery carrier of cytotoxic fatty acid molecules into tumor and bacterial cells across the cell membrane. Perhaps in the future the complexes of α-LA with oleic acid will be used for development of new anti-cancer drugs.
Topics: Animals; Antineoplastic Agents; Humans; Hydrogen-Ion Concentration; Lactalbumin; Neoplasms; Oleic Acid
PubMed: 32825311
DOI: 10.3390/biom10091210 -
American Journal of Respiratory and... May 2023In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was...
In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO removal (ECCOR), provided oxygenation remains acceptable. To compare the effects of ECCOR and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Twenty-four pigs with moderate to severe hypoxemia (Pa:Fi ⩽ 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCOR (0.4 L/min), or mechanical ventilation alone. [Formula: see text]o, [Formula: see text]co, gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; < 0.001), worse oxygenation (Pa:Fi = 125 ± 14 vs. 151 ± 11 mm Hg; < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm HO; = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCOR (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; = 0.003). [Formula: see text]o and [Formula: see text]co, irrespective of lung injury model, were lower during ECMO, resulting in lower Pa and [Formula: see text]e but worse respiratory elastance compared with ECCOR (64 ± 27 vs. 40 ± 8 cm HO/L; < 0.001). ECMO was associated with better oxygenation, lower [Formula: see text]o, and better hemodynamics. ECCOR may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.
Topics: Animals; Acute Lung Injury; Carbon Dioxide; Hydrochloric Acid; Hypertension, Pulmonary; Oleic Acid; Respiration, Artificial; Swine
PubMed: 36848321
DOI: 10.1164/rccm.202212-2194OC -
Current Opinion in Chemical Biology Oct 2022Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as... (Review)
Review
Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as alkynes (CC), nitriles (CN), and carbon-deuterium (C-D) bonds, have been employed in recent years as Raman tags to detect target molecules in cells. In this article, we review some recent advances in applications using deuterated fatty acids for lipid analysis, such as investigation of tumor-selective cytotoxicity of γ-linolenic acid (GLA), simultaneous two-color imaging of stearate and oleate using deuterated and protonated alkynes, Raman hyperspectral imaging, and analyses of the physical properties of lipids through spectral unmixing of the C-D vibrational frequencies. In addition, we review some advanced methods for observing intracellular metabolic activities, such as de novo lipogenesis from deuterium-labeled precursors.
Topics: Alkynes; Carbon; Deuterium; Fatty Acids; Nitriles; Oleic Acid; Spectrum Analysis, Raman; Stearates; gamma-Linolenic Acid
PubMed: 35792373
DOI: 10.1016/j.cbpa.2022.102181 -
Cell Communication and Signaling : CCS Oct 2023Abnormal platelet activation is a key factor in the occurrence and development of thrombotic diseases. However, the physiological mechanisms that underlie platelet...
BACKGROUND
Abnormal platelet activation is a key factor in the occurrence and development of thrombotic diseases. However, the physiological mechanisms that underlie platelet homeostasis remain unclear. Oleic acid, one of the most abundant lipids in the human diet, has potential antithrombotic effects. This study aimed to investigate the effects of oleic acid on platelet activation and thrombosis.
METHODS
Platelet aggregation, ATP release, and fibrinogen spread were evaluated to determine the role of oleic acid in platelet activation. A ferric chloride-induced carotid injury model was used to establish the effect of oleic acid on thrombus formation in vivo. Western blotting analysis and transfection experiments were performed to determine the mechanisms involved in this process.
RESULTS
Oleic acid inhibited platelet aggregation, granule release, and calcium mobilization. Furthermore, it inhibited the spread of platelets on fibrinogen. We also found that oleic acid delayed arterial thrombosis in mice, as demonstrated in a murine model of ferric chloride-induced carotid artery thrombosis. The molecular mechanism of its inhibition of platelet activity may be through the Syk-PLCγ2 and CaMKKβ/AMPKα/VASP pathways. In addition, we demonstrated that the phosphorylation of AMPK at Ser496 was an important mechanism of platelet activation.
CONCLUSIONS
Our study showed that oleic acid inhibits platelet activation and reduces thrombogenesis by inhibiting the phosphorylation of multiple signaling molecules, offering new insights into the research and development of antiplatelet drugs. Video Abstract.
Topics: Humans; Mice; Animals; Oleic Acid; Platelet Activation; Blood Platelets; Thrombosis; Phosphorylation; Collagen; Fibrinogen
PubMed: 37817162
DOI: 10.1186/s12964-023-01276-0 -
MBio Apr 2023The intracellular membrane domain (IMD) is a laterally discrete region of the mycobacterial plasma membrane, enriched in the subpolar region of the rod-shaped cell....
The intracellular membrane domain (IMD) is a laterally discrete region of the mycobacterial plasma membrane, enriched in the subpolar region of the rod-shaped cell. Here, we report genome-wide transposon sequencing to discover the controllers of membrane compartmentalization in Mycobacterium smegmatis. The putative gene showed the most significant effect on recovery from membrane compartment disruption by dibucaine. Enzymatic analysis of Cfa and lipidomic analysis of a deletion mutant (Δ) demonstrated that Cfa is an essential methyltransferase for the synthesis of major membrane phospholipids containing a C monomethyl-branched stearic acid, also known as tuberculostearic acid (TBSA). TBSA has been intensively studied due to its abundant and genus-specific production in mycobacteria, but its biosynthetic enzymes had remained elusive. Cfa catalyzed the -adenosyl-l-methionine-dependent methyltransferase reaction using oleic acid-containing lipid as a substrate, and Δ accumulated C oleic acid, suggesting that Cfa commits oleic acid to TBSA biosynthesis, likely contributing directly to lateral membrane partitioning. Consistent with this model, Δ displayed delayed restoration of subpolar IMD and delayed outgrowth after bacteriostatic dibucaine treatment. These results reveal the physiological significance of TBSA in controlling lateral membrane partitioning in mycobacteria. As its common name implies, tuberculostearic acid is an abundant and genus-specific branched-chain fatty acid in mycobacterial membranes. This fatty acid, 10-methyl octadecanoic acid, has been an intense focus of research, particularly as a diagnostic marker for tuberculosis. It was discovered in 1934, and yet the enzymes that mediate the biosynthesis of this fatty acid and the functions of this unusual fatty acid in cells have remained elusive. Through a genome-wide transposon sequencing screen, enzyme assay, and global lipidomic analysis, we show that Cfa is the long-sought enzyme that is specifically involved in the first step of generating tuberculostearic acid. By characterizing a deletion mutant, we further demonstrate that tuberculostearic acid actively regulates lateral membrane heterogeneity in mycobacteria. These findings indicate the role of branched fatty acids in controlling the functions of the plasma membrane, a critical barrier for the pathogen to survive in its human host.
Topics: Humans; Dibucaine; Mycobacterium; Stearic Acids; Fatty Acids; Oleic Acid; Methyltransferases
PubMed: 36976029
DOI: 10.1128/mbio.03396-22