High Oleic Acid Diet Research Articles

Enhancing Immune-Mediated Radiotherapy Efficacy in Murine Models of Head and Neck Cancer through Peroxisome Proliferator-Activated Receptor Modulation

The tumor microenvironment (TME) in HPV-unrelated head and neck cancer (HNC) is considered to be immunologically "cold," and immunometabolic adaptations to radiotherapy (RT) can exacerbate these conditions and lead to radioresistance. Peroxisome proliferator-activated receptor-α (PPARα) agonism may improve the immune response to RT by reducing glucose scarcity through upregulation of fatty acid utilization in cancer cells. Our clinical trial data shows that high serum oleic acid (OA), a PPAR ligand, correlates with response to radioimmunotherapy. Orthotopic buccal tumor implantations of MOC2 and LY2 HNC cell lines were performed in C57BL/6 and BALB/c mice, respectively. Mice were placed on a high OA diet (38% kcal from OA) 3 weeks prior to tumor implantation. Control diet consisted of 1% kcal from OA. In vitro RT was performed to characterize the metabolic effects on the cancer cell lines. For in vivo studies, tumors were irradiated upon reaching 100 mm^3 with three 8 Gy fractions, given every 4-5 days. The PPARα agonist fenofibrate (FF, 100mg/kg/day) was given via oral gavage or intraperitoneal injection starting 5 days after RT. Tumor volume and overall survival were measured as objective outcomes, and flow cytometry was used to characterize the immune landscape of the tumor, blood, and lymph nodes. Mass spectrometry was employed for bulk proteomics and metabolomics on serum samples, and stable isotope labeling was performed on CD8 T cells from treated mice ex vivo. Extracellular flux analyses were performed on tumor cells and CD8 T cells to determine metabolic phenotypic changes. In vitro cytotoxicity was met for MOC2 and LY2 cancer cells in 100 uM FF and OA in comparison to solvent (p<0.01). Extracellular flux analyses show that RT upregulates the glycolytic phenotype of MOC2 and LY2 cancer cells; and that FF and/or OA decrease the glycolytic capacity of the cancer cells. Ex vivo extracellular flux analyses showed increased glycolytic capacity of CD8 T cells in mice treated with FF in comparison to RT alone. RT in combination with FF significantly improved tumor volume response in comparison to RT alone (mean 99.4 vs 182.7 mm^3, p = 0.001) and was comparable to combination radioimmunotherapy (with anti-PDL1 therapy; mean 99.4 vs. 132.3 mm^3). Unexpectedly, OA negated this improvement in efficacy in both MOC2 and LY2 tumor models; mice on the high OA diet had significantly higher average body weight (p<0.01). Significant changes in adaptive immune response were observed within the TME with the addition of FF. This was mirrored by changes in serum metabolomics. PPARα agonism improved the efficacy of RT in murine HNC models and could be considered in future translational clinical trial design.

Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response

Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both invitro and invivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.

Dietary saturated fat and monounsaturated fat have reversible effects on brain function and the secretion of pro-inflammatory cytokines in young women

BackgroundPrevious literature suggests that a higher ratio of palmitic acid (PA)/oleic acid (OA) in the diet induces inflammation, which may result in deficient brain insulin signaling, and, secondarily, impaired physical activity, sleep efficiency, and cognitive functioning. ObjectiveWe hypothesized that lowering the typical dietary PA/OA would affect the activation of relevant brain networks during a working memory task and would also lower secretion of pro-inflammatory cytokines. DesignIn 12 female subjects participating in a randomized, cross-over trial comparing 3-week high PA diet (HPA) and low PA and a high OA diet (HOA), we evaluated functional magnetic resonance imaging (fMRI) using an N-back test of working memory, cytokine secretion by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), and plasma cytokine concentrations. ResultsBrain activation during the HPA diet compared to the HOA diet was increased in regions of the basal ganglia including the caudate and putamen (p<0.005). In addition, compared to the HOA diet, during the HPA diet, the plasma concentrations of IL-6 (p=0.04) and IL-1β (p=0.05) were higher, and there was a higher secretion of IL-18 (p=0.015) and a trend for higher IL-1β secretion (p=0.066) from LPS-stimulated PBMCs. ConclusionsThe HPA diet resulted in increased brain activation in the basal ganglia compared to the HOA diet as well as increased secretion of pro-inflammatory cytokines. These data provide evidence that short-term (2week) diet interventions impact brain network activation during a working memory task and that these effects are reversible since the order of the study diets was randomized. These data are consistent with the hypothesis that lowering the dietary PA content via substitution with OA also could affect cognition.

Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans

Epidemiologic evidence has suggested that diets with a high ratio of palmitic acid (PA) to oleic acid (OA) increase risk of cardiovascular disease (CVD). To gain additional insights into the relative effect of dietary fatty acids and their metabolism on CVD risk, we sought to identify a metabolomic signature that tracks with diet-induced changes in blood lipid concentrations and whole-body fat oxidation. We applied comprehensive metabolomic profiling tools to biological specimens collected from 18 healthy adults enrolled in a crossover trial that compared a 3-wk high-palmitic acid (HPA) with a low-palmitic acid and high-oleic acid (HOA) diet. A principal components analysis of the data set including 329 variables measured in 15 subjects in the fasted state identified one factor, the principal components analysis factor in the fasted state (PCF1-Fasted), which was heavily weighted by the PA:OA ratio of serum and muscle lipids, that was affected by diet (P < 0.0001; HPA greater than HOA). One other factor, the additional principal components analysis factor in the fasted state (PCF2-Fasted), reflected a wide range of acylcarnitines and was affected by diet in women only (P = 0.0198; HPA greater than HOA). HOA lowered the ratio of serum low-density lipoprotein to high-density lipoprotein (LDL:HDL) in men and women, and adjustment for the PCF1-Fasted abolished the effect. In women only, adjustment for the PCF2-Fasted eliminated the HOA-diet effect on serum total- and LDL-cholesterol concentrations. The respiratory exchange ratio in the fasted state was lower with the HPA diet (P = 0.04), and the diet effect was eliminated after adjustment for the PCF1-Fasted. The messenger RNA expression of the cholesterol regulatory gene insulin-induced gene-1 was higher with the HOA diet (P = 0.008). These results suggest that replacing dietary PA with OA reduces the blood LDL concentration and whole-body fat oxidation by modifying the saturation index of circulating and tissue lipids. In women, these effects are also associated with a higher production and accumulation of acylcarnitines, possibly reflecting a shift in fat catabolism.

Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood

The Western diet increases risk of metabolic disease. We determined whether lowering the ratio of saturated fatty acids to monounsaturated fatty acids in the Western diet would affect physical activity and energy expenditure. With the use of a balanced design, 2 cohorts of 18 and 14 young adults were enrolled in separate randomized, double-masked, crossover trials that compared a 3-wk high-palmitic acid diet (HPA; similar to the Western diet fat composition) to a low-palmitic acid and high-oleic acid diet (HOA; similar to the Mediterranean diet fat composition). All foods were provided by the investigators, and the palmitic acid (PA):oleic acid (OA) ratio was manipulated by adding different oil blends to the same foods. In both cohorts, we assessed physical activity (monitored continuously by using accelerometry) and resting energy expenditure (REE). To gain insight into a possible mood disturbance that might explain changes in physical activity, the Profile of Mood States (POMS) was administered in cohort 2. Physical activity was higher during the HOA than during the HPA in 15 of 17 subjects in cohort 1 (P = 0.008) (mean: 12% higher; P = 0.003) and in 12 of 12 subjects in the second, confirmatory cohort (P = 0.005) (mean: 15% higher; P = 0.003). When the HOA was compared with the HPA, REE measured during the fed state was 3% higher for cohort 1 (P < 0.01), and REE was 4.5% higher in the fasted state for cohort 2 (P = 0.04). POMS testing showed that the anger-hostility score was significantly higher during the HPA (P = 0.007). The replacement of dietary PA with OA was associated with increased physical activity and REE and less anger. Besides presumed effects on mitochondrial function (increased REE), the dietary PA:OA ratio appears to affect behavior. The second cohort was derived from a study that was registered at clinicaltrials.gov as R01DK082803.

Oleic acid and peanut oil high in oleic acid reverse the inhibitory effect of insulin production of the inflammatory cytokine TNF-α both in vitro and in vivo systems

BackgroundChronic inflammation is a key player in pathogenesis. The inflammatory cytokine, tumor necrosis factor-alpha is a well known inflammatory protein, and has been a therapeutic target for the treatment of diseases such as Rheumatoid Arthritis and Crohn's Disease. Obesity is a well known risk factor for developing non-insulin dependent diabetes melitus. Adipose tissue has been shown to produce tumor necrosis factor-alpha, which has the ability to reduce insulin secretion and induce insulin resistance. Based on these observations, we sought to investigate the impact of unsaturated fatty acids such as oleic acid in the presence of TNF-α in terms of insulin production, the molecular mechanisms involved and the in vivo effect of a diet high in oleic acid on a mouse model of type II diabetes, KKAy.MethodsThe rat pancreatic beta cell line INS-1 was used as a cell biological model since it exhibits glucose dependent insulin secretion. Insulin production assessment was carried out using enzyme linked immunosorbent assay and cAMP quantification with competitive ELISA. Viability of TNF-α and oleic acid treated cells was evaluated using flow cytometry. PPAR-γ translocation was assessed using a PPRE based ELISA system. In vivo studies were carried out on adult male KKAy mice and glucose levels were measured with a glucometer.ResultsOleic acid and peanut oil high in oleic acid were able to enhance insulin production in INS-1. TNF-α inhibited insulin production but pre-treatment with oleic acid reversed this inhibitory effect. The viability status of INS-1 cells treated with TNF-α and oleic acid was not affected. Translocation of the peroxisome proliferator- activated receptor transcription factor to the nucleus was elevated in oleic acid treated cells. Finally, type II diabetic mice that were administered a high oleic acid diet derived from peanut oil, had decreased glucose levels compared to animals administered a high fat diet with no oleic acid.ConclusionOleic acid was found to be effective in reversing the inhibitory effect in insulin production of the inflammatory cytokine TNF-α. This finding is consistent with the reported therapeutic characteristics of other monounsaturated and polyunsaturated fatty acids. Furthermore, a diet high in oleic acid, which can be easily achieved through consumption of peanuts and olive oil, can have a beneficial effect in type II diabetes and ultimately reverse the negative effects of inflammatory cytokines observed in obesity and non insulin dependent diabetes mellitus.

High Linoleic Acid, Low Vegetable, and High Oleic Acid, High Vegetable Diets Affect Platelet Activation Similarly in Healthy Women and Men

Upregulation of protein kinase C (PKC), an important enzyme in platelet activation, could be one step toward platelet hyperactivity. PKC activation can be modulated by dietary components in vitro, but few data are available concerning the in vivo effects. In this strictly controlled human dietary intervention, the influence of dietary unsaturated fatty acids and vegetable compounds on platelet activation was investigated. A high linoleic acid diet (10% of energy) with small amounts of vegetables (no berries or apples) was consumed by 9 women and 4 men (24.1 +/- 3.9 y), and was compared with a high oleic acid diet (12% of energy) with considerable amounts of vegetables, berries and apples consumed by 8 women and 4 men (24.2 +/- 5.5 y). Subjects were healthy Finnish volunteers. Compliance with the experimental protocol was good, as indicated by changes in plasma fatty acids and concentrations of vitamin C, beta-carotene and alpha-tocopherol. No differences between groups were seen in indices of platelet activation, including platelet aggregation, total PKC activity and distribution of PKC isoenzymes alpha, beta(II) and delta. The results indicate that in apparently healthy and fairly young subjects with adequate vitamin intakes, diets differing markedly in their amounts of linoleic and oleic acids, and vegetables, berries and apples do not differ in platelet activation.

A high-stearic acid diet does not impair glucose tolerance and insulin sensitivity in healthy women

Results in epidemiological and experimental studies suggest that a diet rich in saturated fat may affect insulin sensitivity. However, no published data are available on the effect of stearic acid in this respect. Therefore, we examined the effects of a high—stearic acid diet and a high—oleic acid diet on glucose metabolism, serum lipids and lipoproteins, and blood coagulation factors in 15 healthy female subjects. Subjects followed the two experimental diets for 4 weeks according to a randomized crossover design. Both experimental diet periods were preceded by consumption of a baseline diet for 2 weeks. The diets provided 36% of energy (E%) as fat. In the experimental diets, 5 E% stearic or oleic acid was substituted for 5 E% of saturated fatty acids in the baseline diet. After the experimental diets, no differences were found in the insulin sensitivity index (mean ± SEM, 5.4 ± 1.9 v 5.2 ± 1.6 × 10 −4 min −1 · μU −1 · mL −1, nonsignificant [NS]), glucose effectiveness (0.026 ± 0.006 v 0.026 ± 0.003 min −1, NS), or first-phase insulin reaction ([FPIR] 368 ± 57 v 374 ± 66 mU/L · min, NS). The concentration of serum lipids and lipoproteins and blood coagulation factors did not differ after the diet periods. In conclusion, a diet rich in stearic acid did not deteriorate glucose tolerance or insulin action in young healthy female subjects as compared with a diet rich in oleic acid.

Fatty Acid Composition of Salmonid Muscle Changes in Response to a High Oleic Acid Diet1–4

Substitution of high oleic acid sunflower oil for herring oil in formulated salmonid diets affected the fatty acid composition of muscle, liver and visceral fat from coho salmon (Oncorhynchus kisutch) and rainbow trout (O. mykiss). Fish were fed diets containing either high oleic acid sunflower oil or herring oil as the supplemental lipid source (12.4 g/100 g diet) for 1-2 mo. Muscle from fish fed the sunflower oil diet had twice the concentration of oleic acid (approximately 25 g/100 g lipid) as muscle from fish fed the herring oil diet (approximately 12 g/100 g lipid). The maximum concentration of oleic acid in the muscle was obtained after only 2 wk of feeding the sunflower oil diet. Oleic acid concentrations in liver and visceral fat of fish fed the sunflower oil diet were significantly higher than in fish fed the herring oil diet. Rainbow trout fed the sunflower oil diet for 4 wk maintained the higher oleic acid concentrations in muscle and liver when deprived of feed for 2 wk compared with fish fed the herring oil diet. These data indicated that accumulation of oleic acid in coho salmon and rainbow trout muscle was fairly rapidly achieved when a high oleic acid diet was fed. The differences between the fish receiving the two dietary treatments in fatty acid composition and in concentrations of thiobarbituric acid-reactive substances in muscle stored at refrigerated temperatures were consistent with previously reported differences in aroma perceived by a sensory panel.

Oleic acid-induced cholelithiasis in the rabbit: conversion of dietary oleic acid to cholestanol as a cause of calcium-bile salt gallstones.

Rabbits fed a diet rich in oleic acid develop gallstones consisting of calcium salts of (5 alpha)-glyco-allodeoxycholic acid. To study the metabolic pathway of oleic acid, we followed the changes in plasma, hepatic and biliary lipids in this animal model. In addition, to also determine the role played by intestinal microflora on biliary lipid metabolism, we added kanamycin to the oleic acid diet. Oleic acid-fed rabbits rapidly developed hypercholesterolemia. This was associated with an increase in liver 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, accumulation of cholesterol as well as cholestanol in the liver and progressive saturation of cholesterol in bile. [14C]oleic acid fed orally to rabbits was recovered in liver extracts as both cholesterol and cholestanol. With oleic acid feeding, there was a progressive increase in glyco-allodeoxycholic acid culminating in the formation of gallstones. Kanamycin supplement to the oleic acid diet resulted in the same changes in plasma and hepatic sterol metabolism compared with oleic acid-fed rabbits. There was, however, a striking difference in the biliary bile acid profile. Kanamycin supplementation dramatically reduced the proportion of 5 alpha-dihydroxy bile acids, increased the proportion of 5 beta-trihydroxy bile acids and completely abolished gallstone formation. We postulate that, in the rabbit, oleic acid is used as a carbon source for cholesterol synthesis, and a high oleic acid diet increases hepatic cholesterogenesis. Hepatic cholesterol is then metabolized to form cholestanol, followed by (5 alpha)-glyco-allocholic acid which is secreted into bile and transformed by gut bacteria to form (5 alpha)-allodeoxycholic acid. Kanamycin abolished gallstone formation by inhibiting intestinal bacterial dehydroxylation.

Cholesterol metabolism in rabbits with oleic acid-induced cholelithiasis.

SummaryCholesterol metabolism has been studied in rabbits with bile acid gallstones induced by feeding a high oleic acid diet. Lithogenic rabbits showed hypercholesterolemia, compared with control rabbits, which was accompanied by a striking increase in the liver cholesterol concentration. The lithogenic diet contained no supplementary cholesterol and hepatic cholesterol synthesis was markedly inhibited. Since intestinal cholesterol synthesis was unchanged in lithogenic rabbits, it is suggested that the increase in plasma and liver cholesterol concentrations was due to increased absorption of cholesterol by the presence of 15% oleic acid in the lithogenic diet. The significance of the raised plasma and liver cholesterol concentrations in relation to the 2-3 fold increase in cholestanol concentration in the livers of lithogenic rabbits remains to be elucidated.The authors are grateful to Mr. A. Shaw for technical assistance.