Beneficial effects of flaxseed oil and fish oil diet are through modulation of different hepatic genes involved in lipid metabolism in streptozotocin nicotinamide induced diabetic rats

Dietary omega 3 fatty acids have been demonstrated to have positive physiological effects on lipid metabolism, cardiovascular system and insulin resistance. Type 2 diabetes (T2DM) is known for perturbations in fatty acid metabolism leading to dyslipidemia. Our objective was to investigate beneficial effects of dietary flaxseed oil and fish oil in streptozotocin nicotinamide induced diabetic rats. Thirty-six adult, male, Wistar rats were divided into six groups: three diabetic and three non-diabetic. Diabetes was induced by an injection of nicotinamide (110 mg/kg) and STZ (65 mg/kg). The animals received either control, flaxseed oil or fish oil (10 percent w/w) enriched diets for 35 days. Both diets lowered serum triglycerides and very low density lipoprotein cholesterol levels and elevated serum high density lipoprotein cholesterol levels in diabetic rats, while serum total cholesterol and LDL C levels remained unaffected. Both the diets increased omega 3 levels in plasma and RBCs of diabetic rats. Flaxseed oil diet significantly up-regulated the key transcription factor peroxisome proliferator-activated receptor a (PPARa ) and down regulated sterol regulatory element binding protein 1 (SREBP1) in diabetic rats, which would have increased beta oxidation of fatty acids and concomitantly reduced lipogenesis respectively, thereby reducing TG levels. Fish oil diet, on the contrary lowered serum TG levels without altering PPARa while it showed a non significant reduction in SREBP1 expression in diabetic rats. Another key finding of the study is the activation of D5 and D6 desaturases in diabetic rats by flaxseed oil diet or fish oil diets, which may have resulted in an improved omega 3 status and comparable effects shown by both diets. The reduced expression of Liver fatty acid binding protein in diabetic rats was restored by fish oil alone, while both diets showed equal effects on adipocyte fatty acid binding protein expression. We also observed down regulation of atherogenic cytokines tumor necrosis factor a and interleukin6 by both the diets. In conclusion, dietary flaxseed oil and fish oil have therapeutic potential in preventing lipid abnormalities in T2DM. (Authors abstract)

Type 2 diabetes mellitus (T2DM) is associated with a varied array of biochemical and physiological anomalies, especially in the liver, including abnormal carbohydrate, lipid and protein metabolism. The abnormalities in lipid metabolism result in higher levels of circulating free fatty acids, hypertriglyceridemia and lower levels of high-density lipoprotein cholesterol (HDL-C) in T2DM patients. Several studies have demonstrated that omega 3 fatty acids can improve lipid metabolism by lowering serum TG. Omega 3 fatty acids may improve lipid metabolism through regulation of PUFA metabolism, thereby altering transcription factors like peroxisome proliferator-activated receptor-a (PPARa), sterol regulatory element binding protein1 (SREBP1) and their downstream genes like delta 5desaturase (D5D), delta 6 desaturase (D6D) and atherogenic pro inflammatory cytokines like tumor necrosis factor a (TNFa) and interleukin6 (IL6). In the present study, the effect of dietary flaxseed oil and fish oil on serum lipids and fatty acid profiles in streptozotocin nicotinamide (STZ NIC) diabetic rats was assessed. The effects of these diets on hepatic expression of transcription factors and genes involved in fatty acid metabolism were determined.  The administration of STZ along with nicotinamide in rats results in a condition, which is similar to T2DM in humans. The flaxseed oil diet and fish oil diet reduced serum TG and VLDL-C levels in STZ-NIC rats. Here both diets increased HDLC levels in diabetic rats. Both the diets did not show any effect on serum TC and LDLC levels in diabetic rats. Also, in control rats, neither flaxseed oil diet nor fish oil diet have any effect on the lipid profile. Thus, both the diets have similar effects on serum lipid profile. Equivalent levels of omega 3 fatty acids were found in plasma of diabetic rats fed flaxseed oil or fish oil diets. Whereas diabetic rats fed flaxseed oil diet showed higher levels of omega 3 fatty acids in RBCs than that shown by fish oil fed diabetic rats.

The activation of PPARa has been shown to stimulate beta oxidation of fatty acids, thereby reducing serum TG level.  PPARa activation has a therapeutic value in T2DM patients in order to control diabetic dyslipidemia. Flaxseed oil diet up regulated hepatic PPARa along with an increase in HDLC levels and a decrease in TG levels in diabetic rats. Thus, it seems that these effects of flaxseed oil diet are mediated via PPARa. Down regulation of SREBP1 in the liver has a therapeutic value in treating diabetic hepatic steatosis and carbohydrate induced hypertriglyceridemia. Here flaxseed oil diet decreased serum TG levels, along with down-regulation of hepatic SREBP1.  The present data suggest different mechanisms for the
hypotriglyceridemic effect of flaxseed oil and fish oil diets.
Flaxseed oil diet demonstrated the activation of PPAR-a  which would enhance b oxidation and suppression of SREBP1, which would reduce lipogenesis.

In this study, both diets up regulated D5D and D6D expression in diabetic rats. The key finding  is the enhanced activation of both these genes by flaxseed oil diet than that by fish oil diet, thus explaining the higher levels of EPA and DHA in RBCs of diabetic rats on flaxseed oil diet. The u regulation of D6D by flaxseed oil diet in control animals was significant and reiterates the role of flaxseed oil in elevating omega 3 status. The effect of flaxseed oil diet on desaturase expression could be attributed to its activation of PPARa.

The anti inflammatory effects of omega 3 fatty acids result in down regulation of TNFa and IL6, thus arresting the progress of various cardiac and vascular disorders. In the present study,
flaxseed oil or fish oil diets down regulated TNFa and IL6 in livers of diabetic rats.

In conclusion, both diets show a ‘TG lowering’ effect in STZ NIC diabetic rats. Flaxseed oil diet may have brought about this effect via modulation of PPARa and SREBP1, while fish oil diet showed a ‘TG lowering’ effect via modulation of SREBP1 and LFABP. Both diets improved omega 3 fatty acid levels in plasma and RBCs of diabetic rats, probably via up regulation of D5D and D6D genes. Both flaxseed oil and fish oil diets down regulated the expression of TNFa, IL6 and AFABP in livers of diabetic rats. Alterations lipid metabolism and inflammation contribute substantially to the pathology of T2DM.  Flaxseed oil or fish oil can potentially correct these metabolic issues, and their dietary supplementation has a therapeutic value in preventing irregularities in lipid metabolism in T2DM. (Editors comments)