Substitution of linoleic acid with α-linolenic acid or long chain n-3 polyunsaturated fatty acid prevents Western diet induced nonalcoholic steatohepatitis.

Key Findings

Nonalcoholic fatty liver disease (NAFLD) is chronic liver disease defined as the fat accumulation in the hepatocytes (≥5% of the total weight) in the absence of excessive alcohol consumption. NAFLD is characterized by ectopic fat accumulation in hepatocytes (steatosis), which is relatively benign. However, approximately 20% of the individuals with simple steatosis develop nonalcoholic steatohepatitis (NASH) which may further progress into liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Substitution of linoleic acid with α-linolenic acid or long chain n-3 polyunsaturated fatty acid prevents Western diet induced nonalcoholic steatohepatitis. In the Western diet, the level of n-6 PUFA is significantly higher than the n-3 PUFA. High levels of n-6 PUFA in the Western diet could potentiate inflammatory response and may induce NASH. In the present study by mimicking typical Western diet, the impact of substitution of n-6 PUFA with n-3 PUFA (varying n-6:n-3 ratio) on the development of NASH was examined. Previous studies demonstrated that compared to n-6:n-3 ratios of 200, 50 and 10, substitution of LA with ALA (n-6:n-3 ratio of 2) or LC n-3 PUFA (n-6:n-3 ratio of 5) prevented sucrose induced insulin resistance and dyslipidemia. Hence, n-6:n-3 ratios of 200 (representing high n-6 PUFA and n-3 PUFA deficient), 2 and 5 were selected. The results of the study demonstrated that partial replacement of LA with ALA (n-6: n-3 ratio of 2) or LC n-3 PUFA (n-6:n-3 ratio of 5) attenuated Western diet induced NASH. The protective effect of n-3 PUFA supplementation include attenuation of insulin resistance and glucose intolerance, optimization of plasma and liver lipid levels, mitigation of hepatic oxidative stress and inflammation, and improvements of aminotransferase activities and histological score. In the present study, both ALA and LC n-3 PUFA supplementation prevented the HFHF induced hepatic oxidative stress by improving the antioxidant status through restoring the antioxidant enzyme activities and GSH level. In the present study, substituting LA with ALA (n-6: n-3 ratio of 2) has been shown to increase the incorporation of LC n-3 PUFA at the expense of LC n-6 PUFA in liver phospholipids, suggesting the competitive interaction and inhibition of the desaturation and elongation of LA to LC n-6 PUFA and preferential conversion of ALA to LC n-3 PUFA. In conclusion, the results of the present study demonstrated that substitution of dietary linoleic acid with α-linolenic acid (n-6:n-3 ratio of 2) or LC n-3 PUFA (n-6:n-3 ratio of 5) protects against the development of Western diet induced NASH as evidenced by improved liver histology, decreased liver and plasma lipids and reduced plasma aminotransferase levels. The protective effect of n-3 PUFA supplementation was attributed to the marked reduction in hepatic oxidative stress and proinflammatory cytokines. The present study also highlights the importance of balancing the n-6 and n-3 PUFA in the diet through suitable blending of vegetable oils for the prevention and management of diet related chronic diseases including NAFLD

ABSTRACT

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.