Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes

2007 ◽  
Vol 293 (2) ◽  
pp. E576-E586 ◽  
Author(s):  
Wen Guo ◽  
Siu Wong ◽  
Weisheng Xie ◽  
Tianluo Lei ◽  
Zhijun Luo
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Er Stress ◽  
Intracellular Signaling ◽  
Unsaturated Fatty Acids ◽  
Glycogen Synthase ◽  
Prolonged Incubation ◽  
Apoptotic Effect ◽  
Induced Apoptosis

Although fatty acids enhance preadipocyte differentiation in the presence of adequate hormone cocktails, little is known regarding their effects in the absence of these hormones. We have now shown that palmitate, a common long-chain saturated fatty acid, induced apoptosis in both mouse 3T3-L1 and rat primary preadipocytes grown in a normal serum-containing medium. Treatment of preadipocytes with palmitate induced multiple endoplasmic reticulum (ER) stress responses, evidenced by increased protein content of CHOP and GRP78 and splicing of XBP-1 mRNA, as well as altered phosphorylation of eIF2α and increased phosphorylation of JNK and Erk1/2. Intriguingly, palmitate induced an early activation of Akt but diminished both Akt activation and its protein mass after prolonged incubation (>6 h). In association with these changes, palmitate reduced expression of β-catenin and its downstream target, c-Myc and cyclin D1, two key prosurvival proteins. Overexpression of constitutively active Akt did not block the apoptotic effect of palmitate. Cotreatment with unsaturated fatty acids (oleate, linoleate) or with LiCl (a glycogen synthase kinase-3β inhibitor) attenuated the palmitate-induced apoptosis. Subsequent analysis suggested that the unsaturated fatty acids probably counteracted palmitate by reducing, not eliminating, ER stress, whereas LiCl probably improved viability by activating the Wnt signaling pathway. Cotreatment of palmitate with a standard adipogenic hormone cocktail also abolished the apoptotic effect and promoted adipocyte differentiation. Collectively, our results suggest that palmitate causes multiple cellular stresses that may lead to apoptosis in preadipocytes in the absence of adipogenic stimuli, highlighting the importance of exogenous hormones in directing cell fate in response to increased fatty acid influx.

scholarly journals Docosahexaenoic and Eicosapentaenoic Acids Prevent Altered-Muc2 Secretion Induced by Palmitic Acid by Alleviating Endoplasmic Reticulum Stress in LS174T Goblet Cells

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2179
Author(s):  
Quentin Escoula ◽  
Sandrine Bellenger ◽  
Michel Narce ◽  
Jérôme Bellenger
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Goblet Cells ◽  
The Impact

Diets high in saturated fatty acids (FA) represent a risk factor for the development of obesity and associated metabolic disorders, partly through their impact on the epithelial cell barrier integrity. We hypothesized that unsaturated FA could alleviate saturated FA-induced endoplasmic reticulum (ER) stress occurring in intestinal secretory goblet cells, and consequently the reduced synthesis and secretion of mucins that form the protective mucus barrier. To investigate this hypothesis, we treated well-differentiated human colonic LS174T goblet cells with palmitic acid (PAL)—the most commonly used inducer of lipotoxicity in in vitro systems—or n-9, n-6, or n-3 unsaturated fatty acids alone or in co-treatment with PAL, and measured the impact of such treatments on ER stress and Muc2 production. Our results showed that only eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids protect goblet cells against ER stress-mediated altered Muc2 secretion induced by PAL, whereas neither linolenic acid nor n-9 and n-6 FA are able to provide such protection. We conclude that EPA and DHA could represent potential therapeutic nutrients against the detrimental lipotoxicity of saturated fatty acids, associated with type 2 diabetes and obesity or inflammatory bowel disease. These in vitro data remain to be explored in vivo in a context of dietary obesity.

Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells

2006 ◽  
Vol 291 (2) ◽  
pp. E275-E281 ◽  
Author(s):  
Yuren Wei ◽  
Dong Wang ◽  
Farran Topczewski ◽  
Michael J. Pagliassotti
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Liver Cells ◽  
Caspase Activity ◽  
Dna Laddering ◽  
Er Homeostasis

Accumulation of lipids in nonadipose tissues can lead to cell dysfunction and cell death, a phenomenon known as lipotoxicity. However, the signaling pathways and mechanisms linking lipid accumulation to cell death are poorly understood. The present study examined the hypothesis that saturated fatty acids disrupt endoplasmic reticulum (ER) homeostasis and promote apoptosis in liver cells via accumulation of ceramide. H4IIE liver cells were exposed to varying concentrations of saturated (palmitate or stearate) or unsaturated (oleate or linoleate) fatty acids. ER homeostasis was monitored using markers of the ER stress response pathway, including phosphorylation of IRE1α and eIF2α, splicing of XBP1 mRNA, and expression of molecular chaperone (e.g., GRP78) and proapoptotic (CCAAT/enhancer-binding protein homologous protein) genes. Apoptosis was monitored using caspase activity and DNA laddering. Palmitate and stearate induced ER stress, caspase activity, and DNA laddering. Inhibition of caspase activation prevented DNA laddering. Unsaturated fatty acids did not induce ER stress or apoptosis. Saturated fatty acids increased ceramide concentration; however, inhibition of de novo ceramide synthesis did not prevent saturated fatty acid-induced ER stress and apoptosis. Unsaturated fatty acids rescued palmitate-induced ER stress and apoptosis. These data demonstrate that saturated fatty acids disrupt ER homeostasis and induce apoptosis in liver cells via mechanisms that do not involve ceramide accumulation.

Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis

2014 ◽  
Vol 306 (3) ◽  
pp. C279-C290 ◽  
Author(s):  
Jing Zhang ◽  
Yuan Li ◽  
Shujun Jiang ◽  
Hao Yu ◽  
Wei An
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Regulatory Element ◽  
Initiation Factor ◽  
Free Radical Scavengers ◽  
Nonalcoholic Fatty Liver ◽  
Transfected Cells ◽  
Hepatic Stimulator Substance ◽  
Induced Apoptosis

Although the potential pathogenesis of nonalcoholic fatty liver disease (NAFLD) is unclear, increasing evidence indicates that endoplasmic reticulum (ER) stress may link free fatty acids to NAFLD. Since we previously reported that hepatic stimulator substance (HSS) could protect the liver from steatosis, this study is aimed to investigate whether HSS protection could be related with its inhibition on ER stress. The HSS gene was stably transfected into BEL-7402 hepatoma cells and effectively expressed in ER. The palmitic acid (PA)-induced heptocyte lipotoxicity was reproduced in the HSS-transfected cells, and HSS alleviation of the ER stress and apoptosis were subsequently examined. The results showed that PA treatment led to a heavy accumulation of fatty acids within the cells and a remarkable increase in reactive oxygen species (ROS). However, in the HSS-expressing cells, production of ROS was inhibited and ER stress-related marker glucose-regulated protein 78 (GRP-78), sterol regulatory element-binding protein (SREBP), anti-phospho-PRK-1ike ER kinase (p-PERK), anti-phospho-eukaryotic initiation factor 2α (p-eIF2α), and anti-C/EBP homologous protein (CHOP) were downregulated compared with the wild-type or mutant HSS-transfected cells. Furthermore, PA treatment severely impaired the activity of sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), leading to imbalanced calcium homeostasis during ER stress, which could be rescued in the HSS-trasfected cells. The protection provided by HSS to the SERCA is identical to that observed with N-acetyl-l-cysteine (NAC) and sodium dimercaptopropane sulfonate (Na-DMPS), which are two typical free radical scavengers. As a consequence, the rate of ER stress-mediated apoptosis in the HSS-expressing cells was significantly reduced. In conclusion, the protective effect of HSS against ER stress may be associated with the removal of ROS to restore the activity of the SERCA.

scholarly journals The effect of dietary fats on the composition of the liver endoplasmic reticulum and oxidative drug metabolism

1979 ◽  
Vol 41 (3) ◽  
pp. 465-475 ◽  
Author(s):  
Catherine T. Hammer ◽  
E. D. Wills
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Linoleic Acid ◽  
Acid Composition ◽  
Unsaturated Fatty Acids ◽  
High Rate ◽  
Oxidative Demethylation ◽  
Maize Oil

1. The dependence of the rate of oxidative demethylation in the liver endoplasmic reticulum on the fatty acid composition of the endoplasmic reticulum has been studied by varying the lipid content of the diet.2. The rate of oxidative demethylation was markedly dependent on the percentage of linoleic acid (18:2) incorporated into the membrane. Feeding diets containing (g/kg) 100 coconut oil, 100 lard or 100 maize oil caused respectively the incorporation of 7.6, 10.3 and 25.1% linoleic acid (18:2) and a demethylation rate of 3.26, 3.15 and 5.03 nmol formaldehyde/min per mg protein. Feeding 100 g herring oil/kg diet caused incorporation of only 5.1% C18:2 but also 27.2% ωw3 unsaturated fatty acids, including 8.7% eicosapentaenoic acid (20:5) and 17.0% docosahexaenoic acid (22.6) and caused a very high rate of oxidative demethylation (6.53 nmol formaldehyde/min per mg protein).3. Destruction of the polyunsaturated fatty acids in herring oil by irradiation with 400 krad caused incorporation of a smaller quantity of ωw3 unsaturated acids into the endoplasmic reticulum and decreased the rate of oxidative demethylation (4.83 nmol formaldehyde/min per mg protein).4. The inductive effects of phenobarbitone on oxidative demethylation were partially dependent on changes in the fatty acid composition of the endoplasmic reticulum. Phenobarbitone (100 mg/kg) increased the percentage of C18:2 from 25.1 to 29.4% in rats given a maize-oil diet, increased the percentage of C20:5 from 8.7 to 10.3% in rats given a herring-oil diet and decreased the percentage of arachidonic acid (20:4) and C22:6 in rats given a lard, maize-oil, herring-oil or irradiated-herring-oil diet.5. Intraperitoneal α-tocopherol (50 mg/kg) increased the percentage of C20:4 from 11.1 to 13.1% in rats given a lard diet and from 5.9 to 7.3% in rats given a herring-oil diet.6. It is concluded that dietary C18:2 is an important factor in the regulation of the rate of oxidative demethylation in the liver endoplasmic reticulum but this may be replaced effectively by dietary C20:5 ω3 and C22:6 ω3 acids. Oxidative demethylation is regulated by changes in the fatty acid composition of the membranes of the liver endoplasmic reticulum.

scholarly journals Saturated Fatty Acid-Induced Cytotoxicity in Liver Cells Does Not Involve Phosphatase and Tensin Homologue Deleted on Chromosome 10

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Dong Wang ◽  
Yuren Wei ◽  
Melinda Frye ◽  
Christopher L. Gentile ◽  
Michael J. Pagliassotti
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Fatty Acid ◽  
Endoplasmic Reticulum Stress ◽  
Saturated Fatty Acid ◽  
Liver Cell ◽  
Unsaturated Fatty Acids ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homologue

Liver specific deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) induces steatosis and hypersensitivity to insulin. Saturated fatty acids, which induce endoplasmic reticulum stress and cell death, appear to increase PTEN, whereas unsaturated fatty acids which do not induce endoplasmic reticulum stress or cell death reduce this protein. In the present study, the role of PTEN in saturated fatty acid-induced cytotoxicity was examined in H4IIE and HepG2 liver cells. Palmitate and stearate increased the expression of PTEN, whereas the unsaturated fatty acids, oleate and linoleate, reduced PTEN expression in both cell types. SiRNA-mediated knockdown of PTEN did not increase liver cell triglyceride stores or reduce palmitate- or stearate-mediated ER stress or apoptosis. These results suggest that PTEN does not play a significant role in saturated fatty acid-induced cytotoxicity in these liver cell models and in the absence of insulin.

scholarly journals A role for unsaturated fatty acids in mitochondrial movement and inheritance.

1991 ◽  
Vol 115 (5) ◽  
pp. 1249-1257 ◽  
Author(s):  
L C Stewart ◽  
M P Yaffe
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Unsaturated Fatty Acids ◽  
Yeast Cells ◽  
Temperature Sensitive ◽  
Permissive Temperature ◽  
Prolonged Incubation ◽  
Mitochondrial Movement ◽  
Mitochondrial Transfer ◽  
Mitochondrial Distribution

Yeast cells with the mdm2 mutation display temperature-sensitive growth and defective intracellular mitochondrial movement at the non-permissive temperature. The latter phenotype includes both an absence of mitochondrial transfer into daughter buds of mitotically growing cells and an aberrant mitochondrial distribution in cells exposed to mating pheromone. The wild-type MDM2 gene was cloned by complementation, and DNA sequence analysis revealed a large open reading frame encoding a putative protein of 58.4 kD. The predicted protein sequence is identical to that reported for the yeast OLE1 gene encoding fatty acid desaturase. Unsaturated fatty acid levels are substantially decreased in mdm2 cells after a prolonged incubation at the non-permissive temperature. The addition of oleic acid complements the temperature-sensitive growth and mitochondrial distribution defects of the mutant cells. These results indicate that mdm2 is a temperature-sensitive allele of OLE1 and demonstrate an essential role for unsaturated fatty acids in mitochondrial movement and inheritance.

scholarly journals MAG-DHA Induces Apoptosis and Autophagy in Breast Cancer Cells via Lipid Peroxidation-Mediated Endoplasmic Reticulum Stress

2020 ◽  
Author(s):  
Jin-jie Zhang ◽  
Yong Yang ◽  
Feng Wang ◽  
Wen-ge Yang ◽  
Zuquan zou
Keyword(s):  
Breast Cancer ◽  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Docosahexaenoic Acid ◽  
Er Stress ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Induced Apoptosis

Abstract Background: Epidemiologic and pre-clinical studies have shown that marine n-3 polyunsaturated fatty acids (n-3 PUFAs) elicit promising chemoprevention against breast cancer. Previous studies found that docosahexaenoic acid monoglyceride (MAG-DHA) does not required pancreatic lipase to be absorbed, unlike DHA-triglyceride which needs to be hydrolyzed by sn-1,3’ specific gastric and (colipase-dependent) pancreatic lipases as free fatty acids and monoglycerol prior to intestinal absorption. Therefore, this property confers increased absorption, and thus a better bioavailability when compared with other formulations such as DHA-free fatty acid, DHA-triglycerol (TAG-DHA), or DHA-ethyl ester (EE-DHA). However, the anti-cancer actions of n-3 PUFA monoglyceride on breast cancer remain to be assessed.Methods: SKBR3 and E0771 cells were exposed in vitro to MAG-DHA. Cell viability (by MTT), malondialdehyde (MDA) levels, cell apoptosis and autophagy (by western blot), Beclin1 knockout (by siRNA) was examined. Transmission electron microscopy (TEM) was used for analyzing cell apoptosis and autophagy in vivo breast cancer exnografts. Results: In this study, we showed that docosahexaenoic acid monoglyceride (MAG-DHA) caused oxidative stress as evidenced by MDA accumulation, which triggered endoplasmic reticulum (ER) stress and subsequently induced apoptosis in E0771 and SKBR3 breast cancer cells. In particular, MAG-DHA-induced apoptosis is associated with the activation of the PERK-eIF2α pathway and caspase-12. MAG-DHA treatment also strongly suppressed the growth of E0771 murine breast cancer xenografts, by ER-stress-induced cell apoptosis. In addition, we found that MAG-DHA-induced ER stress concomitantly triggered autophagy in these cancer cells, and the induction of autophagy suppressed its ability to induce apoptotic cell death. Conclusions: Together, our data suggested that MAG-DHA combined with autophagy inhibitors may be a useful therapeutic strategy in treating breast cancer.

EFFECT OF GINGER, LEMURU FISH OIL SAPONIFICATION AND OLIVE OIL ON COMPOSITION FATTY ACID OF BEEF

2014 ◽  
Vol 4 (1) ◽  
pp. 31-39
Author(s):  
Siwitri Kadarsih
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fish Oil ◽  
Olive Oil ◽  
Rice Bran ◽  
Dry Matter ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Omega 3 ◽  
Omega 6

The objective was to get beef that contain unsaturated fatty acids (especially omega 3 and 6), so as to improve intelligence, physical health for those who consume. The study design using CRD with 3 treatments, each treatment used 4 Bali cattle aged approximately 1.5 years. Observations were made 8 weeks. Pasta mixed with ginger provided konsentrat. P1 (control); P2 (6% saponification lemuru fish oil, olive oil 1%; rice bran: 37.30%; corn: 62.70%; KLK: 7%, ginger paste: 100 g); P3 (lemuru fish oil saponification 8%, 2% olive oil; rice bran; 37.30; corn: 62.70%; KLK: 7%, ginger paste: 200 g). Konsentrat given in the morning as much as 1% of the weight of the cattle based on dry matter, while the grass given a minimum of 10% of the weight of livestock observation variables include: fatty acid composition of meat. Data the analyzies qualitative. The results of the study showed that the composition of saturated fatty acids in meat decreased and an increase in unsaturated fatty acids, namely linoleic acid (omega 6) and linolenic acid (omega 3), and deikosapenta deikosaheksa acid.Keywords : 

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