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Journal of Pineal Research Nov 2020Palmitic acid (PA), the main component of dietary saturated fat, has been known to increase in patients with obesity, and PA-induced lipotoxicity may contribute to...
Palmitic acid (PA), the main component of dietary saturated fat, has been known to increase in patients with obesity, and PA-induced lipotoxicity may contribute to obesity-related male infertility. Melatonin has beneficial effects on reproductive processes; however, the effect and the underlying molecular mechanism of melatonin's involvement in PA-induced cytotoxicity in the testes are poorly understood. Our findings showed that lipotoxicity was observed in mouse testes after long-term PA treatment and that melatonin therapy restored spermatogenesis and fertility in these males. Moreover, melatonin therapy suppressed PA-induced apoptosis by modulating apoptosis-associated proteins such as Bcl2, Bax, C-Caspase3, C-Caspase12, and CHOP in type B spermatogonial stem cells. Changes in the expression of endoplasmic reticulum (ER) stress markers (p-IRE1, p-PERK, ATF4) and intracellular Ca levels showed that melatonin relieved PA-induced ER stress. Mechanistically, melatonin stimulated the expression and nuclear translocation of SIRT1 through its receptors and prevented PA-induced ROS production and mitochondrial dysfunction via SIRT1 signaling pathway. Furthermore, melatonin promoted SIRT1-mediated p53 deacetylation, thereby relieving G2/M arrest in response to PA-stimulated DNA damage. Collectively, these findings indicate that melatonin protects the testes from PA-induced lipotoxicity through the activation of SIRT1, which alleviates oxidative stress, ER stress, mitochondrial dysfunction, and DNA damage.
Topics: Animals; Apoptosis; DNA Damage; Endoplasmic Reticulum Stress; Male; Melatonin; Mice; Oxidative Stress; Palmitic Acid; Sirtuin 1
PubMed: 32761924
DOI: 10.1111/jpi.12690 -
Nature Nov 2021Fatty acid uptake and altered metabolism constitute hallmarks of metastasis, yet evidence of the underlying biology, as well as whether all dietary fatty acids are...
Fatty acid uptake and altered metabolism constitute hallmarks of metastasis, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.
Topics: Animals; Cell Line, Tumor; Chromatin; Dietary Fats; Early Growth Response Protein 2; Extracellular Matrix; Female; Galanin; Histones; Humans; Male; Mice; Neoplasm Metastasis; Palmitic Acid; Schwann Cells
PubMed: 34759321
DOI: 10.1038/s41586-021-04075-0 -
Cell Metabolism May 2021Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention....
Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.
Topics: Animals; Benzamides; Cell Cycle Checkpoints; DNA Damage; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endocytosis; Fatty Acids; Fibrosis; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Palmitic Acid; RNA Interference; RNA, Small Interfering; Serum Albumin, Bovine; Sulfones
PubMed: 33951465
DOI: 10.1016/j.cmet.2021.04.004 -
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 -
Life Sciences Dec 2021Prostate cancer is one of the most frequent causes of cancer death in men worldwide, and novel drugs for prostate cancer therapies are still being developed. Palmitic...
AIMS
Prostate cancer is one of the most frequent causes of cancer death in men worldwide, and novel drugs for prostate cancer therapies are still being developed. Palmitic acid is a common saturated long-chain fatty acid that is known to exhibit anti-inflammatory and metabolic regulatory effects and antitumor activities in several types of tumors. The present study aims to explore the antiproliferative and antimetastatic activities of palmitic acid on human prostate cancer cells and the underlying mechanism.
MAIN METHODS
MTT and colony formation assays were utilized to determine the antiproliferative effect of palmitic acid. Cell metastasis was evaluated by wound healing, Transwell migration and invasion assay. The in vivo anticancer effect was assessed by a nude mouse xenograft model of prostate cancer. The involved molecular mechanisms were investigated by flow cytometry and Western blot analysis.
KEY FINDINGS
Palmitic acid significantly suppressed prostate cancer cell growth in vitro and in vivo. Treatment with palmitic acid induced G1 phase arrest, which was associated with downregulation of cyclin D1 and p-Rb and upregulation of p27. In addition, palmitic acid could inhibit prostate cancer cell metastasis, in which suppression of PKCζ and p-Integrinβ1 and an increase in E-cadherin expression might be involved. Furthermore, a mechanistic study indicated that palmitic acid inhibited the key molecules of the PI3K/Akt pathway to block prostate cancer proliferation and metastasis.
SIGNIFICANCE
Our findings suggested the antitumor potential of palmitic acid for prostate cancer by targeting the PI3K/Akt pathway.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; China; Humans; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Palmitic Acid; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 34653428
DOI: 10.1016/j.lfs.2021.120046 -
Inflammation Research : Official... Nov 2019Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR),... (Review)
Review
Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
Topics: Animals; Fatty Acid-Binding Proteins; Humans; Macrophages; Obesity; PPAR gamma; Palmitic Acid; Toll-Like Receptors
PubMed: 31363792
DOI: 10.1007/s00011-019-01273-5 -
International Journal of Molecular... Dec 2019Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce...
Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce pancreatic β-cell dysfunction and cardiac myocyte apoptosis. Under various cellular stresses, the activation of p53 signaling can lead to cell cycle arrest, DNA repair, senescence, or apoptosis, depending on the severity/type of stress. Nonetheless, the precise role of p53 in lipotoxicity induced by palmitic acid is not clear. Here, our results show that palmitic acid induces p53 activation in a dose- and time-dependent manner. Furthermore, loss of p53 makes cells sensitive to palmitic acid-induced apoptosis. These results were demonstrated in human colon carcinoma cells (HCT116) and primary mouse embryo fibroblasts (MEF) through analysis of DNA fragmentation, flow cytometry, colony formation, and Western blots. In the HCT116 p53 cell line, palmitic acid induced greater reactive oxygen species formation compared to the p53 cell line. The reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and reduced glutathione (GSH) partially attenuated apoptosis in the HCT116 p53 cell line but had no obvious effect on the p53 cell line. Furthermore, p53 induced the expression of its downstream target genes, and , in response to ROS induced by palmitic acid. Loss of p21 also leads to more palmitic acid-induced cell apoptosis in the HCT116 cell line compared with HCT116 p53 and HCT116 p53. In a mouse model of obesity, glucose tolerance test assays showed higher glucose levels in p53 mice that received a high fat diet compared to wild type mice that received the same diet. There were no obvious differences between p53 and p53 mice that received a regular diet. We conclude that p53 may provide some protection against palmitic acid- induced apoptosis in cells by targeting its downstream genes in response to this stress.
Topics: Animals; Apoptosis; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance; Fibroblasts; Gene Deletion; HCT116 Cells; Humans; Mice; Palmitic Acid; Reactive Oxygen Species; Tumor Suppressor Protein p53
PubMed: 31842349
DOI: 10.3390/ijms20246268 -
Free Radical Research Jul 2019Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we...
Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we evaluated ability of pterostilbene (PTS), a methoxylated analogue of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated IR in HepG2 cells. PTS prevented reactive oxygen species (ROS) formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 (NOX3) in PA treated HepG2 cells. Hepatic glucose production was used as a measure of IR and PTS reversed PA-mediated increase in hepatic glucose production by reducing expression of genes coding for gluconeogenic enzymes namely glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC); and their transcription factors cAMP response element binding protein (CREB) and fork head class Box O (FOXO1) along with its coactivator peroxisome proliferator-activated receptor gamma co-activator-1 α (PGC1α). PTS reversed PA-mediated activation of c-Jun N-terminal kinase (JNK), which in turn altered insulin signalling pathway by phosphorylating IRS-1 at Ser 307, leading to inhibition of phosphorylation of Akt and GSK-3β. PTS also reduced PA-mediated lipid accumulation by reducing expression of transcription factors SREBP1c and PPARα. SREBP1c activates genes involved in fatty acid and triglyceride synthesis while PPARα activates CPT1, a rate limiting enzyme for controlling entry and oxidation of fatty acids into mitochondria. PTS, however, did not influence PA uptake confirmed by using BODIPY-labelled fluorescent C16 fatty acid analogue. Thus, our data provides a possible mechanistic explanation for reversal of PA-mediated IR in HepG2 cells.
Topics: Hep G2 Cells; Humans; Insulin Resistance; Oxidative Stress; Palmitic Acid; Stilbenes; Triglycerides
PubMed: 31223033
DOI: 10.1080/10715762.2019.1635252 -
Redox Biology Aug 2022Blood-testis barrier (BTB) damage promotes spermatogenesis dysfunction, which is a critical cause of male infertility. Dyslipidemia has been correlated with male...
Blood-testis barrier (BTB) damage promotes spermatogenesis dysfunction, which is a critical cause of male infertility. Dyslipidemia has been correlated with male infertility, but the major hazardous lipid and the underlying mechanism remains unclear. In this study, we firstly discovered an elevation of palmitic acid (PA) and a decrease of inhibin B in patients with severe dyszoospermia, which leaded us to explore the effects of PA on Sertoli cells. We observed a damage of BTB by PA. PA penetration to endoplasmic reticulum (ER) and its damage to ER structures were exhibited by microimaging and dynamic observation, and consequent ER stress was proved to mediate PA-induced Sertoli cell barrier disruption. Remarkably, we demonstrated a critical role of aberrant protein palmitoylation in PA-induced Sertoli cell barrier dysfunction. An ER protein, Calnexin, was screened out and was demonstrated to participate in this process, and suppression of its palmitoylation showed an ameliorating effect. We also found that ω-3 poly-unsaturated fatty acids down-regulated Calnexin palmitoylation, and alleviated BTB dysfunction. Our results indicate that dysregulated palmitoylation induced by PA plays a pivotal role in BTB disruption and subsequent spermatogenesis dysfunction, suggesting that protein palmitoylation might be therapeutically targetable in male infertility.
Topics: Blood-Testis Barrier; Calnexin; Humans; Infertility, Male; Lipoylation; Male; Palmitic Acid; Spermatogenesis
PubMed: 35803125
DOI: 10.1016/j.redox.2022.102380 -
The FEBS Journal Jul 2023Ferroptosis, featuring an iron-dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study...
Ferroptosis, featuring an iron-dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study found that palmitic acid (PA) inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of reactive oxygen species and lipid peroxidation. The ferroptosis inhibitor Ferrostatin-1 but not Z-VAD-FMK (a pan-caspase inhibitor), Necrostatin-1 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA. Subsequently, we verified that PA induces ferroptotic cell death through excess iron as cell death was inhibited by iron chelator deferiprone (DFP), while it was exacerbated by a supplement of ferric ammonium citrate. Mechanistically, PA affects intracellular iron content by inducing endoplasmic reticulum (ER) stress leading to ER calcium release and regulating transferrin (TF) transport through increasing cytosolic calcium levels. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA-induced ferroptosis. Altogether, our findings reveal that PA engages in anti-cancer properties by activating ER stress/ER calcium release/TF-dependent ferroptosis, and PA might serve as a compound to activate ferroptosis in colon cancer cells with high CD36 expression.
Topics: Humans; Ferroptosis; Iron; Calcium; Palmitic Acid; Reactive Oxygen Species; Colonic Neoplasms
PubMed: 36906928
DOI: 10.1111/febs.16772