ABSTRACT
BACKGROUND: Gastric ulcer has been a major cause of morbidity and mortality worldwide, and it has been linked to factors such as nutritional deficiency, smoking, stress, and continuous intake of non-steroidal antiinflammatory drugs (NSAIDs). The search for new anti-ulcer therapeutic agents has been the subject of several studies. Recently, the gastroprotective effect of Celtis iguanaea has been reported, with linoleic acid (LA) responsible for many of the therapeutic effects of this medicinal plant. AIMS: This study aims to investigate the gastroprotective activity and the possible mechanisms in which LA may be involved through different experimental assays in mice. METHODS: The gastroprotective activity of LA was evaluated in the ulcer induced by indomethacin, HCl/EtOH, hypothermic-restraint stress and pyloric ligation. For the investigation of gastroprotective mechanisms, the quantification of the volume (mL), pH and total acidity of gastric secretion were considered. RESULTS: The oral administrations of 25 mg/kg, 50 mg/kg or 100 mg/kg of body weight of LA were capable of protecting the gastric mucosa against HCl/ethanol (10 mL/kg p.o.), and oral/intraduodenal treatment administrations of 50 mg/kg LA showed protection from ulcers induced by indomethacin, hypothermic-restraint stress and pyloric ligation. CONCLUSION: The results of this study show the gastroprotective role of LA in gastric mucosal damage induced by all assayed distresses. The observed gastroprotection possibly occurs due to the mediated increase of mucosal defensive factors.
Subject(s)
Anti-Ulcer Agents , Stomach Ulcer , Animals , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/therapeutic use , Disease Models, Animal , Ethanol/adverse effects , Gastric Mucosa , Humans , Indomethacin/adverse effects , Linoleic Acid/adverse effects , Mice , Plant Extracts/pharmacology , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapyABSTRACT
High levels of soybean oil (SO) in fish diets enriched with linoleic acid (LA, 18:2n-6) could induce strong inflammation. However, the molecular mechanism underlying LA-induced inflammation in the liver of large yellow croaker (Larimichthys crocea) has not been elucidated. Based on previous research, autophagy has been considered a new pathway to relieve inflammation. Therefore, the present study was performed to investigate the role of autophagy in regulating LA-induced inflammation in the liver of large yellow croaker in vivo and in vitro. The results of the present study showed that activation of autophagy in liver or hepatocytes could significantly reduce the gene expression of proinflammatory factors, such as tumor necrosis factor α (TNFα) and interleukin 1ß (IL1ß). The results of the present study also showed that inhibition of autophagy could upregulate the gene expression of proinflammatory factors and downregulate the gene expression of anti-inflammatory factors in vivo and in vitro. Furthermore, autophagy could alleviate LA-induced inflammatory cytokine gene expression in vivo and in vitro, while inhibition of autophagy obtained the opposite results. In conclusion, our study shows that autophagy could regulate inflammation and alleviate LA-induced inflammation in the liver of large yellow croaker in vivo and in vitro for the first time, which may offer considerable benefits to the aquaculture industry and human health.
Subject(s)
Autophagy , Fish Diseases/immunology , Hepatitis, Animal/immunology , Linoleic Acid/adverse effects , Perciformes/immunology , Animal Feed/adverse effects , Animals , Aquaculture , Cells, Cultured , Fish Diseases/chemically induced , Fish Diseases/pathology , Hepatitis, Animal/chemically induced , Hepatitis, Animal/pathology , Hepatocytes/immunology , Liver/immunology , Liver/pathology , Primary Cell Culture , Soybean Oil/adverse effects , Soybean Oil/chemistryABSTRACT
The breakdown of the epidermal barrier and consequent loss of skin hydration is a feature of skin aging and eczematous dermatitis. Few treatments, however, resolve these underlying processes to provide full symptomatic relief. In this study, we evaluated isosorbide di-(linoleate/oleate) (IDL), which was generated by esterifying isosorbide with sunflower fatty acids. Topical effects of IDL in skin were compared with those of ethyl linoleate/oleate, which has previously been shown to improve skin barrier function. Both IDL and ethyl linoleate/oleate downregulated inflammatory gene expression, but IDL more effectively upregulated the expression of genes associated with keratinocyte differentiation (e.g., KRT1, GRHL2, SPRR4). Consistent with this, IDL increased the abundance of epidermal barrier proteins (FLG and involucrin) and prevented cytokine-mediated stratum corneum degradation. IDL also downregulated the expression of unhealthy skin signature genes linked to the loss of epidermal homeostasis and uniquely repressed an IFN-inducible coexpression module activated in multiple skin diseases, including psoriasis. In a double-blind, placebo-controlled trial enrolling females with dry skin, 2% IDL lotion applied over 2 weeks significantly improved skin hydration and decreased transepidermal water loss (NCT04253704). These results demonstrate mechanisms by which IDL improves skin hydration and epidermal barrier function, supporting IDL as an effective intervention for the treatment of xerotic pruritic skin.
Subject(s)
Dermatitis, Atopic/drug therapy , Emollients/administration & dosage , Keratinocytes/drug effects , Skin Cream/administration & dosage , Water Loss, Insensible/drug effects , Adult , Cell Differentiation/drug effects , Cell Differentiation/genetics , Dermatitis, Atopic/pathology , Double-Blind Method , Emollients/adverse effects , Emollients/chemistry , Epidermis/drug effects , Epidermis/pathology , Female , Filaggrin Proteins , Follow-Up Studies , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Isosorbide/administration & dosage , Isosorbide/adverse effects , Isosorbide/chemistry , Keratinocytes/pathology , Linoleic Acid/administration & dosage , Linoleic Acid/adverse effects , Linoleic Acid/chemistry , Middle Aged , Oleic Acid/administration & dosage , Oleic Acid/adverse effects , Oleic Acid/chemistry , Skin Cream/adverse effects , Skin Cream/chemistry , Treatment OutcomeABSTRACT
BACKGROUND: High linoleic acid (LA) intake leads to inflammation that adversely influences health in fish. However, whether the farnesoid X receptor (FXR) could be an effective target for regulating LA-induced inflammation remains unknown. OBJECTIVE: The purpose of this study was to investigate the role of FXR in the regulation of LA-induced inflammation in large yellow croakers. METHODS: Large yellow croakers (initial weight of 10.03 ± 0.02 g) were allocated to 4 groups and fed a fish oil diet (6% FO), a soybean oil diet (6% SO), or the SO diet supplemented with 300 or 900 mg chenodeoxycholic acid (CDCA)/kg for 10 wk. The cultured kidney cell line PCK and primary hepatocytes from large yellow croakers were stimulated by LA (50 µM) after pretreatment with an FXR ligand (GW4064 or CDCA) or transfection with fxr-small interfering RNA (siFXR). mRNA expression of proinflammatory genes in the head kidney and liver tissues, PCK cells, and primary hepatocytes was determined by qPCR. The luciferase reporter assay, electrophoretic mobility shift assay, and immunoprecipitation assay were conducted in HEK 293T cells to determine the transcriptional activity of P65 and protein interactions between P65 and FXR or the small heterodimer partner (SHP). RESULTS: Proinflammatory genes were 93-1180% higher in the SO group compared with the FO group. CDCA supplementation decreased mRNA expression of proinflammatory genes by 17-87% while increasing fxr and shp expression by 120-460%. In PCK cells and primary hepatocytes, ligand-mediated activation of FXR decreased the LA-induced expression of proinflammatory genes by 18-67%, whereas siRNA-mediated knockdown of FXR increased the LA-induced expression of proinflammatory genes by 64-96%. FXR bound to the promoter of shp and regulated its mRNA expression. Both FXR and SHP could bind to P65 to suppress the transcriptional activity of P65. CONCLUSIONS: These results indicate that FXR has anti-inflammatory properties in large yellow croakers by directly and indirectly suppressing NFκB activity.
Subject(s)
Chenodeoxycholic Acid , Inflammation , Linoleic Acid , Perciformes , Receptors, Cytoplasmic and Nuclear , Soybean Oil , Animals , Animal Feed/analysis , Animal Nutritional Physiological Phenomena , Cell Line , Chenodeoxycholic Acid/administration & dosage , Chenodeoxycholic Acid/pharmacology , Diet/veterinary , Fish Oils , Gene Expression Regulation/drug effects , Hepatocytes/drug effects , Inflammation/chemically induced , Inflammation/prevention & control , Inflammation/veterinary , Kidney/cytology , Linoleic Acid/adverse effects , Perciformes/physiology , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Soybean Oil/administration & dosageABSTRACT
Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.
Subject(s)
Diabetes Mellitus/etiology , Gene Expression/drug effects , Hypothalamus/drug effects , Oxytocin/blood , Soybean Oil/adverse effects , Animals , Inflammation/etiology , Linoleic Acid/adverse effects , Male , Mice , Nervous System Diseases/etiology , Obesity/etiology , Stigmasterol/adverse effectsABSTRACT
OBJECTIVES: The aim of this study was to review the association of dietary intake of oleic and linoleic acids (OA and LA, respectively) with depressive symptoms in perimenopausal women. METHODS: This cross-sectional study used data from the Study of Women's Health Across the Nation (SWAN). Linear and logistic regressions and restricted cubic spline models were performed to examine the association of intake of OA and LA with depression. RESULTS: We included 2793 women 42 to 52 y of age in the present study. Intake of the two acids was positively associated with the Center for Epidemiologic Studies Depression Scale (CES-D) scores in unadjusted and age-, race/ethnicity-, total family income- and education-adjusted linear regression model. The fully adjusted regression coefficients were ßâ¯=â¯0.089 and ßâ¯=â¯0.145 for oleic and linoleic acid intake, respectively. OA and LA intake was positively associated with depressive symptoms (CES-D score ≥16) in unadjusted and age-, race/ethnicity-, total family income- and education-adjusted logistic regression model. The fully adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of depressive symptoms were 1.994 (1.298-3.063) and 1.592 (1.047-2.421) for the highest versus lowest quartile of intake of OA and LA, respectively. CONCLUSION: Intake of OA and LA may be positively associated with depressive symptoms in perimenopausal women.
Subject(s)
Depression/etiology , Dietary Fats/adverse effects , Linoleic Acid/adverse effects , Oleic Acid/adverse effects , Perimenopause/psychology , Adult , Cross-Sectional Studies , Eating , Female , Humans , Logistic Models , Middle Aged , Odds Ratio , Women's HealthABSTRACT
The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function. In pregnancy, LA is vital for foetal development. We investigated the effects of elevated LA in H9c2 cardiomyoblasts in vitro and of a high linoleic acid (HLA, 6.21%) or low linoleic acid (LLA, 1.44%) diet during pregnancy in maternal and offspring hearts. H9c2 cell viability was reduced following LA exposure at concentrations between 300 and 1000 µM. HLA diet decreased cannabinoid receptor type 2 (CB2) mRNA expression in foetal hearts from both sexes. However, HLA diet increased CB2 expression in maternal hearts. The mRNA expression of fatty acid amide hydrolase (FAAH) in foetal hearts was higher in females than in males irrespective of diet and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) mRNA expression showed an interaction between diet and sex. Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring's heart.
Subject(s)
Endocannabinoids/metabolism , Fetal Development/physiology , Heart/embryology , Linoleic Acid/adverse effects , Maternal Nutritional Physiological Phenomena , Amidohydrolases/metabolism , Animals , Cardiometabolic Risk Factors , Cell Survival , Diet, High-Fat/adverse effects , Female , Linoleic Acid/administration & dosage , Male , Models, Animal , Myoblasts, Cardiac , Myocardium/cytology , Myocardium/immunology , Myocardium/metabolism , Pregnancy , Receptor, Cannabinoid, CB2/metabolism , Sex Factors , Signal Transduction/immunologyABSTRACT
Evidence suggests that sub-optimal maternal nutrition has implications for the developing offspring. We have previously shown that exposure to a low-protein diet during gestation was associated with upregulation of genes associated with cholesterol transport and packaging within the placenta. This study aimed to elucidate the effect of altering maternal dietary linoleic acid (LA; omega-6) to alpha-linolenic acid (ALA; omega-6) ratios as well as total fat content on placental expression of genes associated with cholesterol transport. The potential for maternal body mass index (BMI) to be associated with expression of these genes in human placental samples was also evaluated. Placentas were collected from 24 Wistar rats at 20-day gestation (term = 21-22-day gestation) that had been fed one of four diets containing varying fatty acid compositions during pregnancy, and from 62 women at the time of delivery. Expression of 14 placental genes associated with cholesterol packaging and transfer was assessed in rodent and human samples by quantitative real time polymerase chain reaction. In rats, placental mRNA expression of ApoA2, ApoC2, Cubn, Fgg, Mttp and Ttr was significantly elevated (3-30 fold) in animals fed a high LA (36% fat) diet, suggesting increased cholesterol transport across the placenta in this group. In women, maternal BMI was associated with fewer inconsistent alterations in gene expression. In summary, sub-optimal maternal nutrition is associated with alterations in the expression of genes associated with cholesterol transport in a rat model. This may contribute to altered fetal development and potentially programme disease risk in later life. Further investigation of human placenta in response to specific dietary interventions is required.
Subject(s)
Diet, High-Fat/adverse effects , Gene Expression Regulation, Developmental , Maternal Nutritional Physiological Phenomena/genetics , Obesity/complications , Placenta/metabolism , Adult , Animals , Cholesterol/metabolism , Disease Models, Animal , Female , Fetal Development/genetics , Gene Expression Profiling , Humans , Linoleic Acid/administration & dosage , Linoleic Acid/adverse effects , Obesity/metabolism , Pregnancy , Rats , Real-Time Polymerase Chain Reaction , alpha-Linolenic Acid/administration & dosage , alpha-Linolenic Acid/adverse effectsABSTRACT
BACKGROUND: The role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD. METHODS: Two-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly (p value < 5 × 10-8) and solely associated with LA, applied to an IHD case (n ≤ 76,014)-control (n ≤ 264,785) study (mainly based on the meta-analysis of CARDIoGRAMplusC4D 1000 Genomes and UK Biobank CAD SOFT GWAS), the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study, lipids from the Global Lipids Genetics Consortium Results (n = 196,475), and reticulocyte count and blood pressure from the UK Biobank (n ≤ 361,194). A weighted median and Mendelian randomization Egger were used for sensitivity analysis. RESULTS: Genetically predicted LA was not associated with IHD or systolic blood pressure. Genetically predicted higher serum LA was associated with lower diabetes (odds ratio (OR) 0.97 per percentage in total fatty acid increase in LA, 95% confidence interval (CI) 0.96 to 0.99) and lower lipids (low-density lipoprotein, high-density lipoprotein, and total cholesterol), but may be associated with higher diastolic blood pressure. The findings were robust to different single nucleotide polymorphism (SNP) selections, analytic methods, and correction for multiple testing. CONCLUSIONS: Our novel study suggests a benefit of LA for diabetes and lipids but no benefit for IHD, blood pressure, or reticulocyte count. Explicating these paradoxical findings would facilitate identification of effective new interventions for diabetes and IHD.
Subject(s)
Linoleic Acid/adverse effects , Mendelian Randomization Analysis/methods , Myocardial Ischemia/chemically induced , Female , Humans , Male , Middle Aged , Risk FactorsABSTRACT
Dietary polyunsaturated fatty acid (PUFA) levels may affect inflammatory responses and lipid metabolism. Gut microbiota diversity is strongly associated with chronic inflammatory disease, diabetes mellitus (DM), and obesity through abnormal energy homeostasis. In this study, the association between metabolic responses and gut microbiota diversity at different dietary n-6/n-3 PUFA ratios was evaluated in DM rats. Obesity and DM were induced in rats by using a high-fat diet and streptozotocin (STZ), respectively. The obese DM rats were assigned to three groups and administered regular (R), high (H), and low (L) n-6/n-3 ratio diets (n-6/n-3 = 6.39, 3.02, and 9.29, respectively) for 6 weeks. Some metabolic parameters and gut microbiota of the rats were analysed. The results revealed that a high linoleic acid diet increased the plasma and kidney interleukin 6 levels, whereas a low n-6/n-3 ratio diet ameliorated blood glucose homeostasis, reduced plasma tumour necrosis factor α levels, and inhibited systematic inflammation. DM rats exhibited low gut microbiota diversity; however, compared with the R group, the L and H groups did not exhibit alterations in the α-diversity (Observed, Chao 1, Shannon and Simpson). The percentage of Firmicutes was lower in the DM groups than in the non-DM group; however, the L group showed a nonsignificantly higher Firmicutes/Bacteroidetes ratio than did the other groups. Thus, a low n-6/n-3 ratio diet can improve blood glucose homeostasis, reduce systematic inflammation, ameliorate glomerular basal membrane thickening, reduce the expression of receptors of advanced glycation end products in renal vessel walls, and prevent diabetic nephropathies.
Subject(s)
Diabetes Mellitus, Experimental/chemically induced , Diet, High-Fat/adverse effects , Dysbiosis/chemically induced , Gastrointestinal Microbiome , Linoleic Acid/adverse effects , Obesity/chemically induced , Animals , Linoleic Acid/administration & dosage , Male , Rats , Rats, Sprague-DawleyABSTRACT
The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (n-6HFD) on CpG methylation of Fxr and prostaglandin-endoperoxide synthase-2 (Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (Apc) and proliferative cyclin D1 (Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the n-6HFD had reduced (60%) Fxr promoter CpG methylation and increased (~50%) Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (Ibabp), small heterodimer protein (Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The n-6HFD reduced Ptgs-2 CpG methylation, increased the expression of Cox-2, and increased Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of Apc was coupled to accumulation of c-JUN and Ccnd1, respectively cofactor and gene targets for the ß-catenin/Wnt signaling pathway. Finally, the n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an n-6HFD epigenetically modifies Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of Ptsg-2 coupled with silencing of Apc and accumulation of C-JUN and Ccnd1 may increase the risk of inflammation and cancer of the colon.
Subject(s)
Colon/drug effects , Colonic Neoplasms/etiology , DNA Methylation/drug effects , Epigenesis, Genetic , Inflammation/etiology , Intestinal Mucosa/drug effects , Linoleic Acid/adverse effects , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli Protein/metabolism , Animals , Bile Acids and Salts/metabolism , Cells, Cultured , Colitis/etiology , Colitis/genetics , Colitis/metabolism , Colon/metabolism , Colon/pathology , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Cyclin D1/genetics , Cyclin D1/metabolism , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Diet, High-Fat/adverse effects , Dietary Fats/administration & dosage , Dietary Fats/adverse effects , Fetal Research , Genes, jun , Humans , Inflammation/genetics , Inflammation/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Linoleic Acid/pharmacology , Mice, Inbred C57BL , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
Dietary fatty acids are associated with the development of many chronic diseases, such as obesity, diabetes, cardiovascular disease, metabolic syndrome, and several cancers. This review explores the literature surrounding the combined and individual roles of n-6 PUFAs linoleic acid (LA) and arachidonic acid (AA) as they relate to immune and inflammatory response, cardiovascular health, liver health, and cancer. The evidence suggests that a pro-inflammatory view of LA and AA may be over simplified. Overall, this review highlights gaps in our understanding of the biological roles of LA, AA and their complex relationship with n-3 PUFA and the need for future studies that examine the roles of individual fatty acids, rather than groups.
Subject(s)
Arachidonic Acid/adverse effects , Arachidonic Acid/metabolism , Linoleic Acid/adverse effects , Linoleic Acid/metabolism , Animals , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Dietary Fats, Unsaturated/adverse effects , Dietary Fats, Unsaturated/metabolism , Gene Knockout Techniques , Humans , Inflammation/chemically induced , Inflammation/genetics , Inflammation/metabolism , Linoleoyl-CoA Desaturase/genetics , Linoleoyl-CoA Desaturase/metabolism , Liver Diseases/etiology , Liver Diseases/genetics , Liver Diseases/metabolism , Neoplasms/chemically induced , Neoplasms/genetics , Neoplasms/metabolismABSTRACT
This study assesses the effects of cyclic fatty acid monomers (CFAM) from heated vegetable oils on oxidative stress and inflammation. Wistar rats were fed either of these four diets for 28 days: canola oil (CO), canola oil and 0.5% CFAM (CC), soybean oil (SO), and soybean oil and 0.5% CFAM (SC). Markers of oxidative stress and inflammation were determined by micro liquid chromatography tandem mass spectrometry (micro-LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA) kits, respectively. Analysis of variance (ANOVA) for a 2 × 2 factorial design was performed to determine the CFAM and oil effects and interactions between these two factors at P ≤ 0.05. For significant interactions, a post hoc multiple comparison test was performed, i.e., Tukey HSD (honest significant difference) test. CFAM induced higher plasma levels of 15-F2t-IsoP (CC, 396 ± 43 ng/mL, SC, 465 ± 75 ng/mL vs CO, 261 ± 23 ng/mL and SO, 288 ± 35 ng/mL, P < 0.05). Rats fed the SC diet had higher plasma 2,3-dinor-15-F2t-IsoP (SC, 145 ± 9 ng/mL vs CC, 84 ± 8 ng/mL, CO, 12 ± 1 ng/mL, and SO, 12 ± 1 ng/mL, P < 0.05), urinary 2,3-dinor-15-F2t-IsoP (SC, 117 ± 12 ng/mL vs CC, 67 ± 13 ng/mL, CO, 15 ± 2 ng/mL, and SO, 18 ± 4 ng/mL, P < 0.05), and plasma IL-6 (SC, 57 ± 10 pg/mL vs CC, 48 ± 11 pg/mL, CO, 46 ± 9 pg/mL, and SO, 44 ± 4 pg/mL, P < 0.05) than the other three diet groups. These results indicate that CFAM increased the levels of markers of oxidative stress, and those effects are exacerbated by a CFAM-high-linoleic acid diet.
Subject(s)
Fatty Acids/pharmacology , Inflammation/metabolism , Oxidative Stress/drug effects , Rapeseed Oil/pharmacology , Soybean Oil/pharmacology , Animals , Biomarkers/blood , Biomarkers/urine , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Fatty Acids/blood , Fatty Acids/chemistry , Inflammation/chemically induced , Interleukin-6/blood , Isoprostanes/metabolism , Isoprostanes/urine , Linoleic Acid/adverse effects , Liver/drug effects , Liver/metabolism , Male , Neuroprostanes/blood , Neuroprostanes/urine , Rapeseed Oil/adverse effects , Rats, Wistar , Soybean Oil/adverse effects , Tandem Mass SpectrometryABSTRACT
Dietary n-6 polyunsaturated fatty acids (PUFA) are widely perceived to promote inflammation and contribute to the development of chronic diseases. This dogma has been recently questioned due to evidence that n-6 PUFA, specifically linoleic acid (LA, 18:2n-6) and arachidonic acid (AA, 20:4n-6), do not appear to activate inflammatory signalling pathways when consumed in moderate amounts. However, delineating the independent roles of different dietary n-6 PUFA in vivo is challenging because LA is continuously converted into AA in a pathway regulated by the fatty acid desaturase 2 (Fads2) gene. The objective of this study was to investigate the independent roles of LA and AA on white adipose tissue (WAT) inflammatory signalling pathways using Fads2-/- mice. We hypothesized that dietary LA would not induce WAT inflammation, unless it was endogenously converted into AA. Male C57BL/6 wild-type (WT) and Fads2-/- mice were fed low-fat isocaloric diets containing either 7% corn oil w/w (CD, containing ~42% LA) or 7% ARASCO oil w/w (AD, containing ~27% AA) for 9 weeks. WAT inflammatory gene expression, protein levels, as well as phospholipid (PL) and triacylglycerol (TAG) fatty acid composition, were analyzed by RT-qPCR, western blots, and gas chromatography, respectively. Fads2-/- mice fed CD had high LA, but little-to-no GLA (18:3n-6), DGLA (20:3n-6), and AA in PLs and TAGs compared to their WT counterparts. In comparison, Fads2-/- and WT mice fed AD showed minimal differences in n-6 PUFA content in serum and WAT, despite having significantly more AA than CD-fed mice. No differences in gene expression for common inflammatory adipokines (e.g. Mcp-1, Ccl5, Tnfα) or key regulators of eicosanoid production (e.g. Cox-2, Alox-12, Alox-15) were detected in WAT between any of the diet and genotype groups. Furthermore, no differences in MCP-1, and total or phosphorylated STAT3 and p38 inflammatory proteins, were observed. Collectively, these results demonstrate that neither LA nor AA promote WAT inflammation when consumed as part of a low-fat diet. Therefore, the existing dogma surrounding n-6 PUFA and inflammation needs to be reconsidered.
Subject(s)
Arachidonic Acid/administration & dosage , Fatty Acid Desaturases/genetics , Inflammation/metabolism , Linoleic Acid/administration & dosage , Adipose Tissue/drug effects , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Arachidonic Acid/adverse effects , Diet, Fat-Restricted/adverse effects , Dietary Fats/metabolism , Fatty Acid Desaturases/metabolism , Fatty Acids, Unsaturated/metabolism , Gene Expression Regulation/drug effects , Inflammation/chemically induced , Inflammation/genetics , Inflammation/pathology , Linoleic Acid/adverse effects , Lipid Metabolism/genetics , Mice , Phospholipids/metabolism , Signal Transduction/drug effects , Triglycerides/metabolismABSTRACT
Alcoholic liver disease is a major human health problem leading to significant morbidity and mortality in the United States and worldwide. Dietary fat plays an important role in alcoholic liver disease pathogenesis. Herein, we tested the hypothesis that a combination of ethanol and a diet rich in linoleic acid (LA) leads to the increased production of oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxyoctadecadienoic acids (HODEs), which contribute to a hepatic proinflammatory response exacerbating liver injury. Mice were fed unsaturated (with a high LA content) or saturated fat diets (USF and SF, respectively) with or without ethanol for 10 days, followed by a single binge of ethanol. Compared to SF+ethanol, mice fed USF+ethanol had elevated plasma alanine transaminase levels, enhanced hepatic steatosis, oxidative stress, and inflammation. Plasma and liver levels of 9- and 13-HODEs were increased in response to USF+ethanol feeding. We demonstrated that primarily 9-HODE, but not 13-HODE, induced the expression of several proinflammatory cytokines in vitro in RAW264.7 macrophages. Finally, deficiency of arachidonate 15-lipoxygenase, a major enzyme involved in LA oxidation and OXLAM production, attenuated liver injury and inflammation caused by USF+ethanol feeding but had no effect on hepatic steatosis. This study demonstrates that OXLAM-mediated induction of a proinflammatory response in macrophages is one of the potential mechanisms underlying the progression from alcohol-induced steatosis to alcoholic steatohepatitis.
Subject(s)
Dietary Fats/adverse effects , Inflammation/pathology , Linoleic Acid/adverse effects , Liver/metabolism , Liver/pathology , Animals , Arachidonate 15-Lipoxygenase/metabolism , Binge Drinking , Body Composition , Cytokines/metabolism , Disease Models, Animal , Ethanol , Linoleic Acids/metabolism , Linoleic Acids, Conjugated/metabolism , Macrophages/metabolism , Metabolome , Mice , Mice, Inbred C57BL , Oxidation-Reduction , Oxidative Stress , RAW 264.7 CellsABSTRACT
BACKGROUND: Obesity is associated with risk of adenocarcinoma in the proximal stomach. We aimed to identify the links between dietary fat and gastric premalignant lesions. METHODS: C57BL/6 mice were fed high fat diet (HFD), and gastric mucosa was histologically analysed. Morphological changes were also analysed using an electron microscope. Transcriptome analysis of purified parietal cells was performed, and non-parietal gastric corpus epithelial cells were subjected to single-cell gene-expression profiling. Composition of gastric contents of HFD-fed mice was compared with that of the HFD itself. Lipotoxicity of free fatty acids (FFA) was examined in primary culture and organoid culture of mouse gastric epithelial cells in vitro, as well as in vivo, feeding FFA-rich diets. RESULTS: During ~8-20 weeks of HFD feeding, the parietal cells of the stomach displayed mitochondrial damage, and a total of 23% of the mice developed macroscopically distinct metaplastic lesions in the gastric corpus mucosa. Transcriptome analysis of parietal cells indicated that feeding HFD enhanced pathways related to cell death. Histological analysis and gene-expression profiling indicated that the lesions were similar to previously reported precancerous lesions identified as spasmolytic polypeptide-expressing metaplasia. FFAs, including linoleic acid with refluxed bile acids were detected in the stomachs of the HFD-fed mice. In vitro, FFAs impaired mitochondrial function and decreased the viability of parietal cells. In vivo, linoleic acid-rich diet, but not stearic acid-rich diet induced parietal-cell loss and metaplastic changes in mice. CONCLUSIONS: Dietary lipids induce parietal-cell damage and may lead to the development of precancerous metaplasia.
Subject(s)
Diet, High-Fat/adverse effects , Dietary Fats/adverse effects , Fatty Acids/adverse effects , Gastric Mucosa/pathology , Parietal Cells, Gastric/pathology , Precancerous Conditions/pathology , Animals , Bile Acids and Salts/metabolism , Cell Death/genetics , Cells, Cultured , Dietary Fats/administration & dosage , Epithelial Cells/pathology , Fatty Acids/administration & dosage , Fatty Acids/metabolism , Fatty Acids, Nonesterified/metabolism , Gastric Juice/metabolism , Gene Expression Profiling , Linoleic Acid/administration & dosage , Linoleic Acid/adverse effects , Linoleic Acid/metabolism , Male , Metaplasia/genetics , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/ultrastructure , Parietal Cells, Gastric/metabolism , Parietal Cells, Gastric/ultrastructure , Precancerous Conditions/genetics , Primary Cell Culture , Stearic Acids/administration & dosage , Stearic Acids/adverse effectsABSTRACT
A significant change in the Western diet, concurrent with the obesity epidemic, was a substitution of saturated fatty acids with polyunsaturated, specifically linoleic acid (LA). Despite increasing investigation on type as well as amount of fat, it is unclear which fatty acids are most obesogenic. The objective of this study was to determine the obesogenic potency of LA vs. saturated fatty acids and the involvement of hypothalamic inflammation. Forty-eight mice were divided into four groups: low-fat or three high-fat diets (HFDs, 45% kcals from fat) with LA comprising 1%, 15% and 22.5% of kilocalories, the balance being saturated fatty acids. Over 12 weeks, bodyweight, body composition, food intake, calorimetry, and glycemia assays were performed. Arcuate nucleus and blood were collected for mRNA and protein analysis. All HFD-fed mice were heavier and less glucose tolerant than control. The diet with 22.5% LA caused greater bodyweight gain, decreased activity, and insulin resistance compared to control and 1% LA. All HFDs elevated leptin and decreased ghrelin in plasma. Neuropeptides gene expression was higher in 22.5% HFD. The inflammatory gene Ikk was suppressed in 1% and 22.5% LA. No consistent pattern of inflammatory gene expression was observed, with suppression and augmentation of genes by one or all of the HFDs relative to control. These data indicate that, in male mice, LA induces obesity and insulin resistance and reduces activity more than saturated fat, supporting the hypothesis that increased LA intake may be a contributor to the obesity epidemic.
Subject(s)
Encephalitis/etiology , Fatty Acids/adverse effects , Linoleic Acid/adverse effects , Weight Gain , Animals , Carbon Dioxide/metabolism , Chemokine CX3CL1/metabolism , Diet, Fat-Restricted , Encephalitis/chemically induced , Encephalitis/pathology , Ghrelin/blood , Glucose/metabolism , Hypothalamus/pathology , Leptin/blood , Male , Mice, Inbred C57BL , Weight Gain/drug effectsABSTRACT
Recently, debate has erupted in both the scientific community and throughout the lay public around whether a low-fat or low-carbohydrate diet is better for weight loss. In other words, is it better to cut fat or cut carbohydrate for weight loss. However, going beyond this debate (fat versus carbohydrate), are questions around whether certain fatty acids are worse for promoting insulin resistance, inflammation, and obesity. The overall evidence in the literature suggests that medium-chain saturated fats (such as lauric acid, found in coconut oil) and monounsaturated fat (oleic acid, found in olive oil) are less likely to promote insulin resistance, inflammation, and fat storage compared to long-chain saturated fatty acids (such as stearic acid found in large quantities in butter, but particularly palmitic acid found in palm oil) especially when consumed on top of a diet moderate in refined carbohydrates. Compared to long-chain saturated fats, lauric acid and oleic acid have an increased fatty acid oxidation rate, are more likely to be burned for energy and less likely to be stored in adipose tissue, and thus promote increased energy expenditure. Omega-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid, as found in vegetable oils may contribute to obesity, whereas omega-3 PUFA may be protective. Importantly, both olive oil as part of a Mediterranean diet, and omega-3 from fish and fish oil have been proven to reduce risk of cardiovascular (CV) events.
Subject(s)
Fatty Acids/metabolism , Inflammation/metabolism , Insulin Resistance/physiology , Obesity/metabolism , Adipose Tissue/cytology , Adipose Tissue/metabolism , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Diet/methods , Diet/statistics & numerical data , Energy Metabolism/physiology , Fatty Acids/adverse effects , Fatty Acids, Omega-3/adverse effects , Fatty Acids, Omega-3/metabolism , Female , Fish Oils/administration & dosage , Fish Oils/adverse effects , Humans , Lauric Acids/adverse effects , Lauric Acids/metabolism , Linoleic Acid/adverse effects , Linoleic Acid/metabolism , Lipid Metabolism/physiology , Male , Oleic Acid/adverse effects , Oleic Acid/metabolism , Olive Oil/administration & dosage , Olive Oil/adverse effects , Stearic Acids/adverse effects , Stearic Acids/metabolismABSTRACT
Omega (n-)3 and n-6 long chain polyunsaturated fatty acids (LCPUFA) accumulation in the infant brain after birth is strongly driven by dietary supply of n-3 and n-6 LCPUFAs and their C18 precursors through breast milk or infant formula. n-3 LCPUFA accretion is associated with positive effects on neurodevelopmental outcome whereas high n-6 LCPUFA accumulation is considered disadvantageous. Maternal diet is crucial for breast milk fatty acid composition. Unfortunately, global increases in linoleic acid (C18:2n-6; LA) intake have dramatically increased n-6 LCPUFA and reduced n-3 LCPUFA availability for breastfed infants. We investigated the effects of reducing maternal dietary LA, or increasing n-3 LCPUFA, during lactation on milk and offspring brain fatty acids in mice. Offspring brain n-3 LCPUFA was higher following both interventions, although effects were mediated by different mechanisms. Because of competitive interactions between n-3 and n-6 fatty acids, lowering maternal LA intake may support neurodevelopment in breastfed infants.
Subject(s)
Brain Chemistry , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Unsaturated/analysis , Lactation/metabolism , Animals , Animals, Newborn , Animals, Suckling/blood , Brain/growth & development , Brain/metabolism , Dietary Supplements , Female , Linoleic Acid/adverse effects , Male , MiceABSTRACT
The global increase in dietary n-6 polyunsaturated fatty acid (PUFA) intake has been suggested to contribute to the rise in obesity incidence. We hypothesized that reduced n-6 PUFA intake during early postnatal life improves adult body composition and metabolic phenotype upon a Western diet challenge. Male offspring of C57Bl/6j mice and Wistar rats were subjected to a control diet (CTRL; 3.16 En% linoleic acid [LA]) or a low n-6 PUFA diet (low LA; 1.36 En% LA) from postnatal days (PNs) 2 to 42. Subsequently, all animals were switched to a Western-style diet (2.54 En% LA) until PN98. We monitored body composition by dual-energy x-ray absorptiometry and glucose homeostasis by an intravenous glucose and insulin tolerance test in rats and by the homeostasis model assessment of insulin resistance (HOMA-IR) in mice. At PN98, plasma lipids, glucose, insulin, and adipokines were measured and adipocyte number and size were analyzed. In mice, the postnatal low-LA diet decreased fat accumulation during the adult Western-style diet challenge (-27% compared with CTRL, P < .001). Simultaneously, it reduced fasting triglyceride levels and lowered fasting resistin and leptin levels. In rats, the low-LA diet did not affect adult body composition, but decreased the number of retroperitoneal adipocytes and increased the number of large adipocytes. In conclusion, lowering dietary n-6 PUFA intake in early life protected against detrimental effects of an obesogenic diet in adulthood on metabolic homeostasis and fat mass accumulation.