Polyunsaturated fatty acids (PUFAs) have been of immense public interest due to their well-characterized beneficial roles in all life stages. PUFAs have been shown to be helpful in the prevention and/or treatment of various pathological conditions such as obesity, diabetes, coronary heart disease, and certain types of inflammatory diseases and cancers. They have also been shown to be important for the development of the brain. Thus, there has been a lot of interest in characterizing the mechanisms by which these fatty acids exert their effects.

“Our review article summarizes the current understanding of how PUFAs function at the nuclear level.”

The last decade has seen a flurry of research regarding the nuclear effects of PUFAs and the emergence of certain nuclear receptors and transcription factors as key mediators of the nuclear actions of PUFAs. Our review article provides a brief history of the identification of these nuclear factors as mediators of PUFA action and also summarizes the key mechanisms whereby these nuclear factors are regulated by PUFAs. Our review is an excellent starting point for scientists unfamiliar with current research on PUFA regulation of gene expression to acquaint themselves with the state of the field as it stands now.

This article is a concise review of known mechanisms of PUFA regulation of gene expression. It highlights work done by our own group as well as several others that have advanced our understanding of how these fatty acids exert their effects at the nuclear level.

PUFAs have been shown to be beneficial in the treatment of various medical conditions, and diets rich in PUFAs, such as in Japan, have been associated with substantially reduced risk for certain chronic conditions such as coronary heart disease. Therefore, it is of great interest to understand the mechanisms through which PUFAs exert their effects so that new treatments for these pathologic states may be devised.

Our review article summarizes the current understanding of how PUFAs function at the nuclear level. It also highlights some avenues for further research that would help fully elucidate the molecular effects of PUFAs.

Understanding the mechanisms by which PUFAs function is critical to developing new targets for pharmacologic intervention. Furthermore, understanding the molecular role of PUFAs could potentially lead to the establishment of nutritional recommendations for PUFA intake for optimal health.

Our lab first became involved in this research through our studies on the regulation of the delta-9 desaturase, stearoyl CoA desaturase-1 (SCD1).

In the late 1980s, Dr. James M. Ntambi and colleagues had characterized the upregulation of SCD1 expression by fat-free diets. In the early 1990s, Dr. Ntambi showed that supplementing the fat-free diets with polyunsaturated—but not saturated or monounsaturated fatty acids—resulted in significant reduction of SCD1 expression.

This led to further studies that established a role for PUFAs in inhibiting SCD1 transcription as well as mRNA stability in vivo as well as in cell culture models. In 1997, our lab described the localization of the PUFA responsive element in the 5’ flanking region of the SCD1 gene. Our interest in characterizing the regulation of the enzyme, SCD1, has since led to a broadening of our research.

More recently, we have examined the effects of various dietary fatty acids and carbohydrates in the regulation of SCD1 and other genes of lipid metabolism, including the lipogenic transcription factor, SREBP-1c. The development in our lab of a mouse with a targeted mutation in the SCD1 gene has been instrumental in furthering our understanding of gene-nutrient interactions in the regulation of SCD1.

While the SCD1 knockout mouse, which has been extensively characterized by our lab, has been invaluable to our investigations, it has also presented us with some unique challenges. The inability of these mice to synthesize monounsaturated fatty acids creates a requirement for them in the diet, thus limiting our ability to perform dietary manipulations. Also, since this mouse lacks SCD1 in all its tissues, it has been challenging to assign certain phenotypes to the effects of SCD1 deficiency in a particular tissue. Ongoing studies in our lab and others, using tissue-specific knock-down methods, should help circumvent this problem.

PUFAs have clearly emerged as therapeutic players in the prevention/treatment of various chronic diseases, as well as being critical to the developing brain. While these effects are clearly desirable, there is also some concern over excess consumption of certain types of PUFAs that give rise to pro-inflammatory and pro-aggregatory metabolites. Therefore, it has been very difficult to establish a valid nutritional recommendation for optimal consumption of these fatty acids.

Understanding the molecular effects of PUFAs will provide opportunities for development of new drugs for combating various diseases. Furthermore, such research will also equip nutrition educators and policymakers with the tools necessary to set a valid recommendation for the dietary consumption of polyunsaturated fatty acids.