Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIM: Injury to hepatocyte mitochondria is common in metabolic dysfunction-associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid-derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency. APPROACH AND RESULTS: The study was performed in transgenic mice for the fat-1 gene, which allows the endogenous replacement of the membrane omega-6-polyunsaturated fatty acid (PUFA) composition by omega-3-PUFA. Transmission electron microscopy revealed that hepatocyte mitochondria of fat-1 mice had more abundant intact cristae and higher mitochondrial aspect ratio. Fat-1 mice had increased expression of oxidative phosphorylation complexes I and II and translocases of both inner (translocase of inner mitochondrial membrane 44) and outer (translocase of the outer membrane 20) mitochondrial membranes. Fat-1 mice also showed increased mitofusin-2 and reduced dynamin-like protein 1 phosphorylation, which mediate mitochondrial fusion and fission, respectively. Mitochondria of fat-1 mice exhibited enhanced oxygen consumption rate, fatty acid ß-oxidation, and energy substrate utilization as determined by high-resolution respirometry, [1- 14 C]-oleate oxidation and nicotinamide adenine dinucleotide hydride/dihydroflavine-adenine dinucleotide production, respectively. Untargeted lipidomics identified a rich hepatic omega-3-PUFA composition and a specific docosahexaenoic acid (DHA)-enriched lipid fingerprint in fat-1 mice. Targeted lipidomics uncovered a higher content of DHA-derived lipid autacoids, namely resolvin D1 and maresin 1, which rescued hepatocytes from TNFα-induced mitochondrial dysfunction, and unblocked the tricarboxylic acid cycle flux and metabolic utilization of long-chain acyl-carnitines, amino acids, and carbohydrates. Importantly, fat-1 mice were protected against mitochondrial injury induced by obesogenic and fibrogenic insults. CONCLUSION: Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.

Ameliorative effects of omega-3 and omega-6 on spermatogenesis, testicular antioxidant status and in vivo fertility index in heat-stressed rats.

The current study aimed to investigate the use of omega-6 (ω6) or omega-3 (ω3) in reducing heat-induced damage to the testicles. This is due to the known detrimental effects of heat and the potential protective properties of ω6 and ω3. In the study, 48 male rats were divided into eight groups, each containing 6 rats. Group I (control) received normal saline. Group 2 was exposed to high temperatures (43 °C for 20 min/day) and also received normal saline for 60 days. Groups 3-7 underwent identical HS conditions and received varying doses of ω6 or ω3 (0.5 mg/kg DHPG, 1 mg/kg DHPG, 5 mg/kg HT, 0.5 mg/kg DHPG + 5 mg/kg HT, and 1 mg/kg DHPG + 5 mg/kg HT), respectively. After 60 days, various tests were conducted on the testicular tissue, sperm quality, oxidative status, gene activity, and in vivo fertility indexes to evaluate the effects of the treatments. Treatment with ω6 and ω3 could reduce abnormal morphology and DNA damage while increasing total and progressive motility, characteristics motility, viability, and plasma membrane functional impairment compared with HS-exposed groups. Antioxidant status levels in testicular tissue were improved after administration of ω6 and ω3. Furthermore, after receiving ω6 and ω3, there were significantly lower expression levels of P53 and Caspase-3 and significantly higher expression levels of Bcl-2 compared to the HS-exposed group. Furthermore, the results showed that administration of ω6 and ω3 to rats exposed to HS could increase their in vivo fertility indexes compared to the group not exposed to HS. According to our data, all doses of ω6 and ω3 (particularly doses of ω6-1.25 and ω3-300) can improve the testicular damage, testicular antioxidant defense mechanism, regulate germ cell apoptosis, and increase in vivo fertility indexes.

Exploring the role of polyunsaturated fatty acid ratios in modulating neuroinflammation in LPS-induced microglia: A comprehensive in vitro analysis.

The study investigated the effect of different omega (ω)- 3 and omega (ω)- 6 polyunsaturated fatty acid (PUFA) ratios on cytokine secretion, cell viability, and microglial cell shape in lipopolysaccharide (LPS)-induced microglia. The addition of PUFAs at different ratios, especially ω-3 and ratios of 7/1 and 2/1 ω-6/ω-3, resulted in a significant increase in the ameboid form of microglial cells, as well as more branching of their distal branches. Microglial cells were treated with varying ratios of PUFAs, and their cytokine secretion was measured. The results showed that all PUFA ratios had lower tumor necrosis factor (TNF)-α secretion than the control group, higher interleukin (IL)- 4 secretion in the ω-6 group, and less IL-10 secretion most down IL-6 secretion in the 7/1 ratio group. The study suggests that determining the appropriate ω-6/ω-3 consumption ratio, especially the 7/1 and 2/1 ratios, may help manage neuroinflammation, develop dietary models in immune-mediated neurodegenerative diseases, and open up new treatment possibilities.

Differential Interventional Effects of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on High Fat Diet-Induced Obesity and Hepatic Pathology.

Current Dietary Guidelines for Americans recommend replacing saturated fat (SFA) intake with polyunsaturated fatty acids (PUFAs) and monosaturated fatty acids (MUFAs) but do not specify the type of PUFAs, which consist of two functionally distinct classes: omega-6 (n-6) and omega-3 (n-3) PUFAs. Given that modern Western diets are already rich in n-6 PUFAs and the risk of chronic disease remains high today, we hypothesized that increased intake of n-3 PUFAs, rather than n-6 PUFAs, would be a beneficial intervention against obesity and related liver diseases caused by high-fat diets. To test this hypothesis, we fed C57BL/6J mice with a high-fat diet (HF) for 10 weeks to induce obesity, then divided the obese mice into three groups and continued feeding for another 10 weeks with one of the following three diets: HF, HF+n-6 (substituted half of SFA with n-6 PUFAs), and HF+n-3 (substituted half of SFA with n-3 PUFAs), followed by assessment of body weight, fat mass, insulin sensitivity, hepatic pathology, and lipogenesis. Interestingly, we found that the HF+n-6 group, like the HF group, had a continuous increase in body weight and fat mass, while the HF+n-3 group had a significant decrease in body weight and fat mass, although all groups had the same calorie intake. Accordingly, insulin resistance and fatty liver pathology (steatosis and fat levels) were evident in the HF+n-6 and HF groups but barely seen in the HF+n-3 group. Furthermore, the expression of lipogenesis-related genes in the liver was upregulated in the HF+n-6 group but downregulated in the HF+n-3 group. Our findings demonstrate that n-6 PUFAs and n-3 PUFAs have differential effects on obesity and fatty liver disease and highlight the importance of increasing n-3 PUFAs and reducing n-6 PUFAs (balancing the n-6/n-3 ratio) in clinical interventions and dietary guidelines for the management of obesity and related diseases.

Altered Plasma Fatty Acids Associate with Gut Microbial Composition in Common Variable Immunodeficiency.

PURPOSE: Fatty acid (FA) abnormalities are found in various inflammatory disorders and have been related to disturbed gut microbiota. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with altered gut microbial composition. We hypothesized that there is an altered FA profile in CVID patients, related to gut microbial dysbiosis. METHODS: Plasma FAs were measured in 39 CVID patients and 30 healthy controls. Gut microbial profile, a food frequency questionnaire, and the effect of the oral antibiotic rifaximin were investigated in CVID patients. RESULTS: The n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) (1.4 [1.0-1.8] vs. 1.9 [1.2-2.5], median (IQR), P < 0.05), and docosahexaenoic acid (DHA) (3.2 [2.4-3.9] vs. 3.5 [2.9-4.3], P < 0.05), all values expressed as weight percent of total plasma FAs, were reduced in CVID compared to controls. Also, n-6 PUFAs (34.3 ± 3.4 vs. 37.1 ± 2.8, mean ± SD, P < 0.001) and linoleic acid (LA) (24.5 ± 3.3 vs. 28.1 ± 2.7, P < 0.0001) and the FA anti-inflammatory index (98.9 [82.1-119.4] vs. 117.0 [88.7-153.1], median (IQR), P < 0.05) were reduced in CVID. The microbial alpha diversity was positively associated with plasma n-6 PUFAs (r = 0.41, P < 0.001) and LA (r = 0.51, P < 0.001), but not n-3 PUFAs (P = 0.78). Moreover, a 2-week course of rifaximin significantly reduced the proportion of n-6 PUFAs (P = 0.04, UNIANOVA). Serum immunoglobulin G (IgG) levels correlated with plasma n-3 PUFAs (rho = 0.36, P = 0.03) and DHA (rho = 0.41, P = 0.009). CONCLUSION: We found a potentially unfavorable FA profile in CVID, related to low IgG levels. High plasma n-6 PUFAs were related to increased gut microbial diversity and altered by rifaximin therapy.

Interaction between ω-6 fatty acids intake and blood cadmium on the risk of low cognitive performance in older adults from National Health and Nutrition Examination Survey (NHANES) 2011-2014.

BACKGROUND: Identifying preventable diets and environmental exposure is essential to ensuring the health of the aging population. This study evaluated the interaction effect between blood cadmium and ω-6 fatty acids intake on low cognitive performance in Americans. METHOD: The data of this cross-sectional study were obtained from the 2011-2012 and 2013-2014 National Health and Nutritional Examination Survey (NHANES). Cognitive performance was measured by the Consortium to Establish a Registry for Alzheimer's Disease test, Animal Fluency Test, and Digit Symbol Substitution Test. Multivariate logistic regression models were used. RESULTS: A total of 1,918 individuals were included, with 467 (24.35%) low cognitive performance. Compared with participants with normal-level blood cadmium, those with high-level blood cadmium had a higher risk of low cognitive performance [odds ratio (OR) was 1.558 with 95% confidence interval (CI): 1.144-2.123]. Low-level ω-6 fatty acids intake was positively associated with low cognitive performance [OR = 1.633 (95%CI: 1.094-2.436)] compared with normal-level intake. Moreover, there was a significant interaction between low-level ω-6 fatty acids intake and high-level blood cadmium on the risk of low cognitive performance (relative excess risk due to interaction: 0.570, 95%CI: 0.208-0.932; the attributable proportion of interaction: 0.219, 95%CI: 0.102-0.336; synergy index: 1.552, 95%CI: 1.189-2.027). CONCLUSIONS: There was a synergistic interaction between low-level ω-6 fatty acids intake and high-level blood cadmium on low cognitive performance. Low-level ω-6 fatty acids intake may amplify the adverse effects of long-term exposure to cadmium on cognitive performance. This may have a certain significance for the prevention of cognitive decline in the elderly.

Synergistic hepatoprotective effects of ω-3 and ω-6 fatty acids from Indian flax and sesame seed oils against CCl4-induced oxidative stress-mediated liver damage in rats.

Flaxseed (FS) and sesame seed (SS) are traditional and functional foods in traditional Indian medicine for treating various disorders. The present study investigated the hepatoprotective effects of bioactive-fatty acids (FAs) from FS and SS against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Pre and post-treatments for 28 consecutive days significantly increased the activities of in vivo antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and peroxidase (POX), whereas, lipid peroxidation (LPO) activity was markedly decreased in a dose-dependent manner in liver and kidneys. A significant reduction was observed in the hematological parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin in the serum of post-treated animals compared to the negative control. The results were confirmed histopathologically. The results suggested that the ω-3 and ω-6 FAs from flaxseed oil (FSO) and sesame seed oil (SSO), respectively, showed potential synergistic hepatoprotective and antioxidant effects that were mediated mainly by ω-3 and ω-6 FAs present in the respective seed oils.

Susceptibility of Female Mice to the Dietary Omega-3/Omega-6 Fatty-Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia.

Maternal intake of omega-3 (n-3 PUFAs) and omega-6 (n-6 PUFAs) polyunsaturated fatty acids impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). The n-3 PUFAs and n-6 PUFAs are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA-deficient diet. The n-3 PUFA-deficient diet reduced the DG volume, AHN, microglia number, and surveilled volume. The diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, as well as the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia.

Omega-6 Polyunsaturated Fatty Acids Enhance Tumor Aggressiveness in Experimental Lung Cancer Model: Important Role of Oxylipins.

Lung cancer is currently the leading cause of cancer death worldwide; it is often diagnosed at an advanced stage and bears poor prognosis. It has been shown that diet is an important environmental factor that contributes to the risk and mortality of several types of cancers. Intake of ω-3 and ω-6 PUFAs plays an important role in cancer risk and progression. Current Western populations have high consumption of ω-6 PUFAs with a ratio of ω-6/ω-3 PUFAs at 15:1 to 16.7:1 This high consumption of ω-6 PUFAs is related to increased cancer risk and progression. However, whether a diet rich in ω-6 PUFAs can contribute to tumor aggressiveness has not been well investigated. We used a murine model of pulmonary squamous cell carcinoma to study the aggressiveness of tumors in mice fed with a diet rich in ω-6 PUFAs and its relationship with oxylipins. Our results shown that the mice fed a diet rich in ω-6 showed a marked increase in proliferation, angiogenesis and pro-inflammatory markers and decreased expression of pro-apoptotic proteins in their tumors. Oxylipin profiling revealed an upregulation of various pro-tumoral oxylipins including PGs, HETEs, DiHETrEs and HODEs. These results demonstrate for the first time that high intake of ω-6 PUFAs in the diet enhances the malignancy of tumor cells by histological changes on tumor dedifferentiation and increases cell proliferation, angiogenesis, pro-inflammatory oxylipins and molecular aggressiveness targets such as NF-κB p65, YY1, COX-2 and TGF-ß.

Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome.

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial ß-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.

The effects of the esterified Quercetin with omega3 and omega6 fatty acids on viability, nanomechanical properties, and BAX/BCL-2 gene expression in MCF-7 cells.

Quercetin is one of the major flavonoids and it appears to have cytotoxic effects on various cancer cells through regulating the apoptosis pathway genes such as BAX and BCL2. Combination of Quercetin (Q) with other compounds can increase its effectiveness. In the present study, the effects of the Quercetin and its esterified derivatives on viability, nanomechanical properties of cells, and BAX/BCL-2 gene expression were investigated. Using the MTT and flow cytometry assays, the cytotoxic potential, apoptosis, and necrosis were investigated. The AFM assay was performed to find the nanomechanical properties of cells as the elastic modulus value and cellular adhesion forces. The BAX/BCL2 gene expression was investigated through the Real-Time PCR. The results showed that the esterification of Quercetin with linoleic acid (Q-LA) and α-linolenic acid (Q-ALA) increased the cytotoxic potential of Q. The elastic modulus value and cellular adhesion forces were increased using the esterified derivatives and the highest ratio of BAX/BCL2 gene expression was observed in Q-LA. Esterified Quercetin derivatives have a higher cytotoxic effect than the un-esterified form in a dose-dependent manner. Esterified derivatives caused the nanomechanical changes and pores formation on the cytoplasmic membrane. One of the internal apoptosis pathway regulation mechanisms of these compounds is increasing the BAX/BCL2 gene expression ratio.

Maternal and Postnatal High Linoleic Acid Diet Impacts Lipid Metabolism in Adult Rat Offspring in a Sex-Specific Manner.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. We aimed to investigate the effect of maternal and postnatal high LA (HLA) diet on plasma FA composition, plasma and hepatic lipids and genes involved in lipid metabolism in the liver of adult offspring. Female rats were fed with low LA (LLA; 1.44% LA) or HLA (6.21% LA) diets for 10 weeks before pregnancy, and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), fed either LLA or HLA diets and sacrificed at PN180. Postnatal HLA diet decreased circulating total n-3 PUFA and alpha-linolenic acid (ALA), while increased total n-6 PUFA, LA and arachidonic acid (AA) in both male and female offspring. Maternal HLA diet increased circulating leptin in female offspring, but not in males. Maternal HLA diet decreased circulating adiponectin in males. Postnatal HLA diet significantly decreased aspartate transaminase (AST) in females and downregulated total cholesterol, HDL-cholesterol and triglycerides in the plasma of males. Maternal HLA diet downregulated the hepatic mRNA expression of Hmgcr in both male and female offspring and decreased the hepatic mRNA expression of Cpt1a and Acox1 in females. Both maternal and postnatal HLA diet decreased hepatic mRNA expression of Cyp27a1 in females. Postnatal diet significantly altered circulating fatty acid concentrations, with sex-specific differences in genes that control lipid metabolism in the adult offspring following exposure to high LA diet in utero.

Omega-3 and Omega-6 polyunsaturated fatty acids stimulate vascular differentiation of mouse embryonic stem cells.

Polyunsaturated fatty acids (PUFAs) and their metabolites may influence cell fate regulation. Herein, we investigated the effects of linoleic acid (LA) as ω-6 PUFA, eicosapentaenoic acid (EPA) as ω-3 PUFA and palmitic acid (PA) on vasculogenesis of embryonic stem (ES) cells. LA and EPA increased vascular structure formation and protein expression of the endothelial-specific markers fetal liver kinase-1, CD31 as well as VE-cadherin, whereas PA was without effect. LA and EPA increased reactive oxygen species (ROS) and nitric oxide (NO), activated endothelial NO synthase (eNOS) and raised intracellular calcium. The calcium response was inhibited by the intracellular calcium chelator BAPTA, sulfo-N-succinimidyl oleate which is an antagonist of CD36, the scavenger receptor for fatty acid uptake as well as by a CD36 blocking antibody. Prevention of ROS generation by radical scavengers or the NADPH oxidase inhibitor VAS2870 and inhibition of eNOS by L-NAME blunted vasculogenesis. PUFAs stimulated AMP activated protein kinase-α (AMPK-α) as well as peroxisome proliferator-activated receptor-α (PPAR-α). AMPK activation was abolished by calcium chelation as well as inhibition of ROS and NO generation. Moreover, PUFA-induced vasculogenesis was blunted by the PPAR-α inhibitor GW6471. In conclusion, ω-3 and ω-6 PUFAs stimulate vascular differentiation of ES cells via mechanisms involving calcium, ROS and NO, which regulate function of the energy sensors AMPK and PPAR-α and determine the metabolic signature of vascular cell differentiation.

Emerging roles of metabolites of ω3 and ω6 essential fatty acids in the control of intestinal inflammation.

The gastrointestinal tract is continuously exposed to the external environment, which contains numerous non-self antigens, including food materials and commensal micro-organisms. For the maintenance of mucosal homeostasis, the intestinal epithelial layer and mucosal immune system simultaneously provide the first line of defense against pathogens and are tightly regulated to prevent their induction of inflammatory responses to non-pathogenic antigens. Defects in mucosal homeostasis lead to the development of inflammatory and associated intestinal diseases, such as Crohn's disease, ulcerative colitis, food allergy and colorectal cancer. The recent discovery of novel dietary ω3 and ω6 lipid-derived metabolites-such as resolvin, protectin, maresin, 17,18-epoxy-eicosatetraenoic acid and microbe-dependent 10-hydroxy-cis-12-octadecenoic acid-and their potent biologic effects on the regulation of inflammation have initiated a new era of nutritional immunology. In this review, we update our understanding of the role of lipid metabolites in intestinal inflammation.

A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.

BACKGROUND: Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.

The effect of maternal dietary fat content and n-6:n-3 ratio on offspring growth and hepatic gene expression in the rat.

n-6 Fatty acids have been shown to exert pro-adipogenic effects, whereas n-3 fatty acids work in opposition. Increasing intakes of linoleic acid (LA; n-6) v. α-linolenic acid (ALA; n-3) in Western diets has led to the hypothesis that consumption of this diet during pregnancy may be contributing to adverse offspring health. This study investigated the effects of feeding a maternal dietary LA:ALA ratio similar to that of the Western diet (9:1) compared with a proposed 'ideal' ratio (about 1:1·5), at two total fat levels (18 v. 36 % fat, w/w), on growth and lipogenic gene expression in the offspring. Female Wistar rats were assigned to one of the four experimental groups throughout gestation and lactation. Offspring were culled at 1 and 2 weeks of age for sample collection. Offspring of dams consuming a 36 % fat diet were approximately 20 % lighter than those exposed to an 18 % fat diet (P < 0·001). Male, but not female, liver weight at 1 week was approximately 13 % heavier and had increased glycogen (P < 0·05), in offspring exposed to high LA (P < 0·01). Hepatic expression of lipogenic genes suggested an increase in lipogenesis in male offspring exposed to a 36 % fat maternal diet and in female offspring exposed to a low-LA diet, via increases in the expression of fatty acid synthase and sterol regulatory element-binding protein. Sexually dimorphic responses to altered maternal diet appeared to persist until 2 weeks of age. In conclusion, whilst maternal total fat content predominantly affected offspring growth, fatty acid ratio and total fat content had sexually dimorphic effects on offspring liver weight and composition.

Association of dietary ω-3 and ω-6 fatty acids intake with cognitive performance in older adults: National Health and nutrition examination Survey (NHANES) 2011-2014.

BACKGROUND: Current evidence on the association of dietary ω-3 and ω-6 fatty acids intake with cognitive performance is inconsistent. Therefore, the aim is to explore the association of dietary ω-3 and ω-6 fatty acids intake with cognitive performance in the U.S. noninstitutionalized population of older adults. METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Intakes of ω-3 and ω-6 fatty acids were obtained through two 24-h dietary recalls and were adjusted by energy. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Word Learning sub-test, Animal Fluency test and Digit Symbol Substitution Test (DSST). For each cognitive test, people who scored lower than the lowest quartile in each age group were defined as having low cognitive performance. Binary logistic regression and restricted cubic spline models were applied to evaluate the association of dietary ω-3 and ω-6 fatty acids intake with cognitive performance. RESULTS: A total of 2496 participants aged 60 years or older were included. In the full-adjusted model, the odds ratios (ORs) with 95% confidence interval (CI) of CERAD test score, Animal Fluency test score and DSST test score were 0.58 (0.38-0.88), 0.68 (0.47-0.99) and 0.59 (0.37-0.92) for the highest versus lowest tertile of dietary ω-3 fatty acids intake, respectively; the ORs with 95% CI of CERAD test score, Animal Fluency test score and DSST test score were 0.48 (0.31-0.75), 0.60 (0.40-0.92) and 0.50 (0.34-0.75) for the highest versus lowest tertile of dietary ω-6 fatty acids intake, respectively. The association between ω-6: ω-3 ratio and cognitive performance was not statistically significant in three tests. In dose-response relationship analysis, L-shaped associations were apparent for ω-3 and ω-6 fatty acids intake with CERAD test score, Animal Fluency test score and DSST test score. CONCLUSIONS: Dietary ω-3 and ω-6 fatty acids intake might be inversely associated with low cognitive performance.

Fatty Acid Mediators in the Tumor Microenvironment.

Patients with cancer frequently overexpress inflammatory cytokines with an associated neutrophilia both of which may be downregulated by diets with high omega-3 polyunsaturated fatty acids (ω-3 PUFA). The anti-inflammatory activity of dietary ω-3 PUFA has been suggested to have anticancer properties and to improve survival of cancer patients. Currently, the majority of dietary research efforts do not differentiate between obesity and dietary fatty acid consumption as mediators of inflammatory cell expansion and tumor microenvironmental infiltration, initiation, and progression. In this chapter, we discuss the relationships between dietary lipids, inflammation, neoplasia and strategies to regulate these relationships. We posit that dietary composition, notably the ratio of ω-3 vs. ω-6 PUFA, regulates tumor initiation and progression and the frequency and sites of metastasis that, together, impact overall survival (OS). We focus on three broad topics: first, the role of dietary lipids in chronic inflammation and tumor initiation, progression, and regression; second, lipid mediators linking inflammation and cancer; and third, dietary lipid regulation of murine and human tumor initiation, progression, and metastasis.

A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet.

A diet high in n-6 polyunsaturated fatty acids (PUFAs) may contribute to inflammation and tissue damage associated with obesity and pathologies of the colon and liver. One contributing factor may be dysregulation by n-6 fatty acids of enterohepatic bile acid (BA) metabolism. The farnesoid X receptor (FXR) is a nuclear receptor that regulates BA homeostasis in the liver and intestine. This study aims to compare the effects on FXR regulation and BA metabolism of a palm oil-based diet providing 28% energy (28%E) from fat and low n-6 linoleic acid (LA, 2.5%E) (CNTL) with those of a soybean oil-based diet providing 50%E from fat and high (28%E) in LA (n-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the Fxrα1 isoform under the control of the intestine-specific Villin promoter (Fxrα1TG) were fed the CNTL or n-6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the n-6HFD supports higher weight gain in both WT and FxrαTG littermates; increases the expression of Fxrα1/2, and peroxisome proliferator-activated receptor-γ1 (Pparγ1) in the small intestine, Fxrα1/2 in the colon, and cytochrome P4507A1 (Cyp7a1) and small heterodimer protein (Shp) in the liver; and augments the levels of total BA in the liver, and primary chenodeoxycholic (CDCA), cholic (CA), and ß-muricholic (ßMCA) acid in the cecum. Intestinal overexpression of the Fxra1TG augments expression of Shp and ileal bile acid-binding protein (Ibabp) in the small intestine and Ibabp in the proximal colon. Conversely, it antagonizes n-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of Cyp7a1; and expression of Pparγ in the small intestine. We conclude that intestinal Fxrα1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of human-specific primary bile acids in the cecum.

Polyunsaturated Fatty Acids of Both the Omega-3 and the Omega-6 Family Abrogate the Cytokine-Induced Upregulation of miR-29a-3p by Endothelial Cells.

Cellular processes fundamentally depend on protein expression control. At this, protein expression is regulated on the transcriptional and the post-transcriptional level. PUFAs are already known to affect gene transcription. The present study was conducted to answer the question whether PUFAs are also able to impact on the miRNA-mediated post-transcriptional fine-tuning of mRNA copy numbers. To this end, cellular miRNA profiles were screened by means of next-generation sequencing and NanoString analysis to compare PUFA-enriched to unsupplemented endothelial cells exposed to an inflammatory milieu. Validation took place by droplet digital PCR, allowing for an absolute quantification of RNA copy numbers. The analyses revealed that the stimulation-induced upregulation of miR-29a-3p is blocked by PUFA enrichment of endothelial cells. What is more, mRNA copy numbers of miR-29a-3p targets, namely the coagulation factors PAI-1, TF, and vWF, as well as the proinflammatory cytokines IL-1ß, IL-6, and IL-8, were reduced in PUFA-enriched endothelial cells compared to unsupplemented cells, counteracting the stimulatory effect of an inflammatory environment. These data hint toward a new mechanism of action by which PUFAs modulate the functionality of endothelial cells. Apparently, the inflammation-modulating properties of PUFAs are also mediated at the post-transcriptional level.