The role of n6 and n3 polyunsaturated fatty acids in the manifestation of the metabolic syndrome in cardiovascular disease and nonalcoholic fatty liver disease

Cardiovascular disease (CVD) and non alcoholic fatty liver disease (NAFLD) are manifestations of the metabolic syndrome. CVD remains the number one cause of mortality in the West, while NAFLD is the most common liver disease. Growing evidence suggests that polyunsaturated fatty acids (PUFA) influence risk factors including circulating lipids and inflammation on the development of CVD and NAFLD. N 6 and n 3 PUFA are comprised of distinct family members, which are increasingly recognized for their individual effects. Therefore, this review examines what is currently known about the specific effects of the major n 3 and n 6 PUFA on CVD and NAFLD. Overall, this review supports a beneficial effect of n  3 PUFA and highlights distinctive effects between alpha linolenic acid found in plant oils relative to marine derived eicosapentaenoic acid and docosahexaenoic acid. This review also highlights contrasting health effects between the n 6 PUFA, linoleic and arachidonic acid. (Authors Abstract)

Cardiovascular disease (CVD) and non alcoholic fatty liver disease (NAFLD) are the vascular and hepatic manifestations of a cluster of metabolic disturbances known collectively as the metabolic syndrome. Both CVD and NAFLD share phenotypic traits including elevated serum lipids and a pro-inflammatory state.  NAFLD is characterized by the result of excessive deposition of lipids and de novo lipid synthesis within hepatocytes leading to simple steatosis. The quality of the diet plays an important role in influencing the development and progression of CVD and NAFLD. Studies have shown a positive association between an increased consumption of EPA and DHA and an improved prognosis of CVD and NAFLD. n 6 PUFA consumption has been shown to increase the composition of AA within adipocyte phospholipids and is associated with an increased risk of CVD.  While there is growing evidence for distinct bioactivity among and between n 3 and n 6 PUFA, most studies do not differentiate effects between individual fatty acids. In particular, the independent effects of ALA and LA have not been extensively studied. The goal of this review is to examine the differential effects of ALA and LA, and their downstream metabolites EPA and DHA and AA on circulating lipids and inflammatory biomarkers in human and experimental models of CVD and NAFLD.

The Multiple Risk Factor Intervention Trial reported that increased ALA in the serum cholesterol esters and phospholipid fractions was independently associated with a significant decrease in the risk of stroke in middle aged men at high risk of CVD;  and subsequent epidemiological studies have reported similar findings.  But the hypocholesterolemic and anti inflammatory effect of ALA on individuals with metabolic related diseases has not been well described. It is hypothesized that the benefits of ALA are derived through its conversion to EPA and DHA or by impeding the production of AA.   In studies in which ALA rich oils were provided to humans ranging from 3 months to 2 years, a beneficial association with reduced risk of acute cardiovascular events, and lower concentrations of inflammatory mediators such as C reactive protein and IL 6 were observed.   A supplementation study lasting 3 months using whole flaxseeds have also found that groups receiving the supplement have lower total and HDL cholesterol levels.  ALA rich oils and flaxseed supplementation appear to reduce risk factors for CVD in comparison to control and high saturated fat diets, Studies were unable to conclude whether it was the ALA content or another nutrient within flaxseed which produced the effects. These studies were not able to provide evidence for the direct effects of ALA, due to conversion of ALA, albeit minimal, to EPA and DHA. Observational studies have found inverse correlations between ALA and plasma markers of inflammation.   Researchers have speculated that the beneficial effects of flaxseed oil supplementation were due to associated increases in cellular EPA content, as a dose response effect could be observed between elevated levels of cellular EPA and reduced production of TNF alpha and IL 6b.  The reviewers conclude that research is necessary to determine the efficacy of ALA rich oils to improve lipoprotein profiles in humans. Studies that have found beneficial effects of ALA in the context of NAFLD often suggest that these effects are solely due to the conversion of ALA to EPA and DHA.  Finally, recent reviews which have attempted to determine the effects of n 3 PUFA on metabolic diseases have focused primarily on the effects of EPA and DHA.  Thus, there remains a need to better understand the mechanisms and action of ALA, independent of its conversion. (Editors comments)