Bioactive Fatty Acids Reduce Development of Gastric Cancer Following Duodenogastric Reflux in Rats

Background: Bioactive fatty acids such as the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the modified fatty acid analogue, tetradecylthioacetic acid (TTA), are known to influence inflammatory processes in the body. Our aim was to investigate if diets containing fish oil (FO) enriched with bioactive fatty acids could affect inflammation and development of glandular stomach carcinogenesis in a duodenogastric reflux (DGR) animal model. We also wanted to evaluate if a high-fat diet might increase the risk of developing gastric cancer compared to a low-fat diet. Methods: 185 rats operated on with a gastroenterostomy were randomly allocated to 5 different treatment groups given: low-fat, high-fat, high-fat + FO, high-fat + TTA or high-fat + FO + TTA. The stomachs were removed after 50 weeks and examined by light microscopy with hematoxylin and eosin staining (HE). Immunohistochemical staining against COX-2, PCNA and p53 was performed when adenocarcinomas were found. The plasma fatty acid profile was determined. Results: Adenocarcinomas developed in 21% of animals fed the low-fat diet, 35% in the high-fat group, 16% in the high-fat + TTA group, 21% in the high-fat + FO group and 8.6% in the high-fat + FO + TTA treatment group. COX-2 and PCNA were positive whereas p53 was negative in the majority of the samples. The anti-inflammatory fatty acid index increased after treatment with FO and in combination with FO and TTA. Conclusion: FO and TTA in combination with a high-fat diet significantly lower the risk of developing adenocarcinomas in rats subjected to duodenogastric reflux. This is most likely due to a selective modulation of inflammation.

Meldonium-induced steatosis is associated with increased delta 6 desaturation and reduced elongation of n-6 polyunsaturated fatty acids

Background and objective Metabolic associated fatty liver disease(MAFLD)is associated with abnormal lipid metabolism.Mitochondrial dysfunction is considered an important factor in the onset of MAFLD,whereas altered fatty acid composition has been linked to the severity of the disease.Tetradecylthioacetic acid(TTA),shown to induce mitochondrial proliferation and alter the fatty acid composition,was used to delay the accumulation of hepatic triacylglycerol.This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet.Methods C57BL/6 mice(n=40)were fed high-carbohydrate diets supplemented with meldonium,TTA,or a combination of meldonium and TTA for 21 days.Lipid levels were determined in liver samples,and fatty acid composition was measured in both liver and plasma samples.Additionally,desaturase and elongase activities were estimated.The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples,whereas carnitines,their precursors,and acylcarnitines were measured in plasma samples.Results The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines.Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA.The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase(D6D;C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6),and increased circulating levels of C18:4n-3 and C18:3n-6(gamma-linolenic acid).TTA mitigated meldonium-induced triacylglycerol levels by 80%and attenuated the estimated D6D activities,and elongation of n-6 polyunsaturated fatty acids(PUFAs).TTA also attenuated the meldonium-mediated reduction of C24:1n-9(nervonic acid),possibly by stimulating Elovl5 and increased elongation of erucic acid(C22:1n-9)to nervonic acid.The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels,while the estimated activities of D6D correlated positively.Conclusion Circulating levels of gamma-linolenic acid,along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities,were associated with hepatic triacylglycerol levels.