Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet may increase the risk of nonalcoholic fatty liver disease (NAFLD). This study investigates the impact of substitution of linoleic acid with α-linolenic acid (ALA) or long chain (LC) n-3 PUFA and hence decreasing n-6:n-3 fatty acid ratio on high fat, high fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were divided into four groups and fed control diet, HFHF diet (n-6:n-3 ratio of 200), HFHF diet with ALA (n-6:n-3 ratio of 2) or HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5) for 24 weeks. Rats fed HFHF diet with n-6:n-3 ratio of 200 resulted in hepatic steatosis, induced glucose intolerance, insulin resistance and oxidative stress accompanied by increase in markers of inflammation, plasma lipids and aminotransferase levels. Histopathological examination of liver further confirmed the establishment of NASH. ALA and LC n-3 PUFA supplementation prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity. Furthermore, n-3 PUFA supplementation attenuated hepatic oxidative stress by restoring antioxidant status, decreased inflammation and preserved hepatic architecture. These finding suggest that decreasing n-6:n-3 ratio prevented HFHF induced NASH by attenuating oxidative stress and inflammation.

Fructose in combination with TFA caused NASH with fibrosis by inducing oxidative stress and inflammation, whereas, fructose in combination with SFA caused simple steatosis, suggesting that the type of fatty acid is more important for the progression of NAFLD.

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Effect of dietary n‐6/n‐3 polyunsaturated fatty acids (PUFA) ratio on the fructose‐induced adipose tissue oxidative and endoplasmic reticulum (ER) stress was not explored previously. Here, we studied the effect of diets containing n‐6 PUFA & α‐linolenic acid (ALA, 18:3 n‐3 PUFA) and n‐6 PUFA & long chain n‐3 PUFA (docosahexanoic acid and eicosapentaenoic acid, DHA and EPA) in the ratio of 2:1 and 5:1 respectively on fructose‐induced oxidative and ER stress in adipose tissue.Weanling Wistar rats were divided in to four groups and fed with diets containing starch (n‐6/n‐3 PUFA ratio 215:1), fructose (n‐6/n‐3 PUFA ratio 215:1) and fructose‐with n‐6/n‐3 PUFA ratio 2:1 (18:3 n‐3 PUFA) and 5:1 (long chain n‐3 PUFA) diets for twenty‐four weeks. Activities of glucose‐6‐phosphate dehydrogenase (G6PDH), glutathione peroxidase (GPx), and catalase and superoxide dismutase (SOD) were measured in visceral adipose tissue along with glutathione levels and lipid peroxidation. Expression of p22 phox gene related oxidative stress was quantified along with ER stress marker gene, GRP78.ALA and long chain (LC) n‐3 PUFA feeding significantly reduced fructose‐induced G6PDH activity to similar extent by 28% (p≤0.01). Both ALA and LC n‐3 PUFA significantly reduced the fructose‐induced SOD activity by 15% and 12% respectively (p≤0.01), whereas they reduced fructose‐induced catalase activity to similar extent by 23.5% (p≤0.05). ALA and long chain (LC) n‐3 PUFA feeding significantly elevated the GPx activity that is reduced by high fructose‐ diet feeding by 14.6% and 12% respectively (p≤0.05) without altering the tissue glutathione levels. Lipid peroxidation, an important determinant of tissue oxidative stress is significantly reduced by both ALA‐ and LC n‐3 PUFA‐enriched diets by 12% and 35% respectively (p≤0.01). p22 phox gene expression is significantly reduced by both ALA and LC n‐3 PUFA by 12% and 33% respectively (p≤0.05) along with ER stress marker, GRP78 by 40% and 30% respectively (p≤0.05).We conclude that replacement of dietary n‐6 PUFA with ALA and LC n‐3 PUFA ameliorates fructose‐induced oxidative and ER stress in visceral adipose tissue. Though both ALA and LC n‐ 3 PUFA significantly reduced fructose‐induced oxidative stress, considering beneficial effects LC n‐3 PUFA on lipid peroxidation and LC n‐3 PUFA exhibited protective nature at less quantity than ALA, we propose that diets rich in LC n‐3 PUFA may protect against fructose‐induced oxidative and ER stress in adipose tissue.Support or Funding InformationThe present study was carried out with the financial support of Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, and Indian Council of Medical Research (ICMR), Government of India. AS was supported by Council of Scientific and Industrial Research (CSIR).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of dietary n‐6/n‐3 polyunsaturated fatty acids (PUFA) ratio on the fructose‐induced visceral obesity and adipose tissue dysfunction was not studied previously. Here we studied the effect of diets containing n‐6 PUFA & α‐linolenic acid (ALA, 18:3 n‐3 PUFA) and n‐6 PUFA & long chain n‐3 PUFA (docosahexanoic acid and eicosapentaenoic acid, DHA and EPA) in the ratio of 2:1 and 5:1 respectively on fructose‐induced metabolic syndrome in the rats.Weanling Wister rats were divided in to four groups and fed with diets containing starch (n‐6/n‐3 PUFA ratio 215:1), fructose (n‐6/n‐3 PUFA ratio 215:1) and fructose‐with n‐6/n‐3 PUFA ratio 2:1 (18:3 n‐3 PUFA) and 5:1 (long chain n‐3 PUFA) diets for twenty‐four weeks. Body composition, adiposity index and adipocyte size were determined along with macrophage infiltration by immunofluorescence. Gene expression of proteins related to pro‐ and anti‐inflammatory cytokines, and pre‐receptor metabolism of glucocorticoids were quantified by quantitative PCR. Plasma fatty acid profile was determined gas chromatography and, circulatory .0lipids and adipokines were measured by kit‐based methods. Insulin resistance was determined by homeostatic measurement of insulin resistance (HOMA‐IR) and oral glucose tolerance test.Both n‐3 PUFA treatments significantly reduced the fructose‐induced visceral obesity and hyperuricemia. ALA and long chain (LC) n‐3 PUFA feeding significantly reduced fructose‐induced macrophage infiltration in adipose tissue, proinflammatory gene expression including monocyte chemoattractant protein 1, E‐selectin, tumor necrosis factor‐α, toll like receptor 2, 4 and corrected circulatory monocyte chemoattractant protein 1 and interleukin‐10 levels. Both n‐3 PUFA treatments significantly reduced fructose‐induced insulin resistance during fasting (HOMA‐IR) and corrected the elevated circulatory adiponectin levels. Interestingly, only LC n‐3 PUFA corrected the insulin resistance after the oral glucose challenge indicated by decreased area under curve for insulin (AUC). Both n‐3 PUFA treatments significantly reduced fructose‐induced gene expression of 11β‐hydroxysteroid dehydrogenase 1, an enzyme involved in pre‐receptor generation of glucocorticoids.We conclude that replacement of dietary n‐6 PUFA with ALA and LC n‐3 PUFA ameliorates fructose‐induced visceral obesity, adipocyte dysfunction and insulin resistance. Though both ALA and LC n‐3 PUFA supplementation significantly reduced fructose‐induced adipose tissue dysfunction, considering beneficial effects LC n‐3 PUFA on insulin resistance and as LC n‐3 PUFA exhibited protective nature at less quantity than ALA, we propose that diets with LC n‐3 PUFA gives better protection against fructose‐induced adipose tissue dysfunction and insulin resistance than the diets with ALA.Support or Funding InformationThe present study was carried out with the financial support of Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, and Indian Council of Medical Research (ICMR), Government of India. AS was supported by Council of Scientific and Industrial Research (CSIR).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.