Flax oil-mediated activation of PPAR-ƴ correlates with reduction of hepatic lipid accumulation in obese spontaneously hypertensive/NDmcr-cp rats, a model of the metabolic syndrome

Flax oil feeding has been proposed to have beneficial effects on the outcome of the metabolic syndrome due to the high n-3 fatty acid content of flax oil; however, the mechanisms of its action remain largely unknown. We investigated the effects of flax oil feeding on hyperlipidaemia, hyperglycaemia, hepatic steatosis and oxidative stress in the spontaneously hypertensive (SHR)/NDmcr-cp rats, a genetic model of the metabolic syndrome. Hepatic gene expression of PPAR-a, PPAR-g and sterol-regulatory element-binding protein-1c was also assessed in order to investigate the possible underlying mechanisms. Obese and lean SHR/NDmcr-cp rats were fed high-fat diets enriched with either lard or flax oil for a period of 4 weeks. Obese rats exhibited higher body weight, liver weight and mesenteric fat-, epididymal fat- and renal fat-pad weights, and also TAG and cholesterol concentrations in serum and VLDL, LDL and HDL fractions, when compared with the lean rats (P<0.001), irrespective of the diets. Concentrations of fasting serum insulin and urinary thiobarbituric acid reactive substances were lower in flax oil-fed obese (FO) rats compared with the lard-fed obese (LO) rats (P<0.01). Flax oil feeding also revealed a significant reduction in hepatic TAG and cholesterol concentrations in obese rats compared with the LO rats (P<0.05). In addition, FO rats exhibited significantly higher hepatic mRNA expression of PPAR-g, which negatively correlated (r 20.98, P<0.05) with their hepatic lipid levels. These findings suggest that flax oil feeding may activate PPAR-g-dependent pathways to alter the hepatic lipid metabolism and to increase insulin sensitivity in the obese SHR/NDmcr-cp rats. (Author's Abstract)
High intake of dietary SFA is associated with increased incidence of CVD, whereas a high intake of PUFA is known to reduce its incidence. Flax oil has gained attention as an important dietary source of n-3 PUFA, especially among the vegetarian populations. ALA consumption by itself has been reported to exert beneficial effects on the clinical outcomes of renal failure, multiple sclerosis, cancer, hypertension and CVD. A number of studies have shown that flax oil supplementation can reduce serum TAG and cholesterol concentrations. Flaxseed oil has anti-inflammatory properties that are mediated by the production of anti-inflammatory cytokines.
Spontaneously hypertensive (SHR)/NDmcr-cp rats exhibit most of the metabolic symptoms observed in patients with the metabolic syndrome. In this study, diets enriched with either flax oil or lard were fed to both obese and lean SHR/NDmcr-cp rats. To gain an insight into the underlying molecular mechanisms, the gene expression of PPAR-a, PPAR-g and sterol-regulatory element-binding protein (SREBP)-1c was also measured, as PPAR-a is known to regulate the expression of genes involved in b-oxidation of fatty acids and SREBP-1c regulates the expression of genes involved in de novo lipogenesis and fatty acid metabolism, while PPAR-g expression has been associated with insulin-sensitising effects. In the present study, FO SHR/NDmcr-cp rats exhibited a significant reduction in the hepatic concentrations of TAG and cholesterol compared with the LO rats. Flax oil feeding was also associated with a significant reduction in the urinary TBARS levels in the obese SHR/NDmcr-cp rats, a marker for the systemic oxidative stress, suggesting that flax oil feeding could prevent inflammatory development of non-alcoholic steatohepatitis. A significant increase in the mRNA expression of liver PPAR-a was observed in the FL rats compared with the LL rats, but not in the FO rats. These findings suggest that the expression of PPAR-a is not associated with reduced hepatic lipid levels in case of the obese SHR/NDmcr-cp rats. The authors speculate that flax oil has beneficial effects by activating the hepatic expression of PPAR-gamma, which  enhances the insulin sensitivity of the liver as well as of the peripheral tissues. Flax oil feeding was associated
with a significant reduction in plasma insulin concentration in the obese SHR/NDmcr-cp rats compared with the LO rats, which appears to support this. Flax oil feeding was associated with lower LDL-cholesterol concentration in lean SHR/NDmcr-cp rats compared with the LL rats. The present study reports that flax oil feeding is associated with a reduction of hepatic lipid accumulation in obese SHR/NDmcr-cp rats.  An increase in the hepatic mRNA expression of PPAR-gamma by flax oil feeding showed a negative correlation with hepatic lipid levels in the obese SHR/NDmcrcp rats. Flaxseed oil feeding also lowered serum insulin levels and systemic oxidative stress in obese SHR/ NDmcr-cp rats. The authors propose that flax oil-mediated activation of PPAR-g and its insulin-sensitising effects result in the reduction of hepatic lipid accumulation in the obese rats. (Editor's comments)