Polyunsaturated fatty acid metabolism in cardiometabolic disease

Polyunsaturated fatty acid metabolism in cardiometabolic disease

A primary focus of research in our lab is to better understand the influence of PUFA metabolism in the development of heart disease and diabetes/insulin resistance. Most of our work in this area has employed in vivo gain- and loss-of-function approaches in rodent models targeting -6 desaturase (encoded by the FADS2 gene), the rate-limiting enzyme in the conversion of dietary essential PUFAs into their long-chain PUFA derivatives. Several projects have evolved over the past 10 years supported by grants from the NHLBI/NIH, American Heart Association, and US Department of Agriculture. The major themes being investigated currently are summarized briefly below.

Delta-6 Desaturase mediates cardiac membrane phospholipid remodeling in heart disease

Polyunsaturated fatty acids (PUFAs) are lipid hydrocarbon chains containing at least two double bonds, derived either from the diet or endogenous biosynthesis from essential PUFA precursors. PUFAs are principal components of cell membrane phospholipids and are widely recognized as bioactive nutrients with broad effects on cardiovascular health.  Studies over the past 40 years have reported a marked redistribution of the specific PUFAs present in cardiac phospholipids associated with aging, chronic ischemia, obesity/diabetes and heart failure.  The pattern of PUFA redistribution is strikingly consistent across species and pathologies, manifesting primarily as a loss of the 18-carbon essential omega-6 PUFA linoleic acid (LA) with reciprocal increases in the long-chain highly unsaturated PUFAs arachidonic acid (AA; omega-6) and/or docosahexaenoic acid (DHA, omega-3).   The mechanism of this phenomenon was unclear until studies in our lab demonstrated its reversal by chronic pharmacological inhibition of delta-6 desaturase (D6D) in rodent models of aging, pressure-overload hypertrophy, and heart failure.  D6D catalyzes rate limiting steps in the conversion of dietary essential PUFAs LA and alpha-linolenic acid (ALA, omega-3), into their long-chain derivatives AA and DHA, respectively, indicating that the redistribution of PUFA in cardiac membranes in disease states results from enhanced activity of D6D catalyzing de novo synthesis of long-chain PUFAs.

Remarkably, D6D inhibition in these animal models also attenuated myocardial hypertrophy, fibrosis, and contractile dysfunction associated with aging, pressure overload and hypertensive heart disease.  The mechanisms responsible for these benefits, including the origin and biological effects of the omega-6 vs. omega-3 PUFA species most affected, remain under investigation in our lab.   Studies to date implicate AA-derived eicosanoids and inflammatory signaling, alterations in hepatic lipid release, and changes in cardiac mitochondrial function as primary modulators of cardiometabolic health by D6D activity.  Current projects are investigating the influence of D6D activity on cardiac mitochondrial membrane composition, Ca2+ tolerance, OXPHOS efficiency and ROS production in response to ischemia/reperfusion stress (heart attack). For these studies, we utilize mice genetically modified to have excess or deficient FADS2 expression, and pharmacological approaches to block D6D activity and related PUFA metabolism enzymes.



FADS2 regulates effects of dietary PUFAs on cardiometabolic risk

The dietary balance of omega-6 (n6) and omega-3 (n3) PUFA has been proposed as an important modulator of cardiometabolic risk and inflammation in humans, but conflicting reports in the literature has limited consensus on dietary recommendations for optimal risk reduction. Studies in our laboratory are testing the hypothesis that variations in the metabolism of dietary essential PUFAs regulate metabolic and cardiovascular responses to the modern “Western” diet.  This idea is supported by animal studies in our lab and altered cardiometabolic risk profiles in populations with polymorphisms in the FADS2 gene encoding delta-6 desaturase, the rate-limiting enzyme in long-chain PUFA synthesis.

To test this hypothesis, we developed mice with global heterozygous knockout (low), wild-type (WT; medium) or mild transgenic overexpressed (high) levels of the murine Fads2 gene. When fed a standard (high-n6 PUFA) chow diet, mice with high Fads2 expression develop progressive obesity, glucose intolerance, and mild hypertension, with lower tolerance to myocardial ischemia (larger heart attacks).  Mice with low Fads2 expression have no overt phenotype when fed a chow diet, but are protected against cardiac ischemia and the cardiometabolic insults induced by consuming a high-fat diet. When mice are fed standardized diets containing dietary essential PUFAs at ~7% kcals provided as a balance of n6 PUFA (as linoleic acid, 18:2n6, from corn oil) and alpha-linolenic acid (18:3n3 from flax oil), cardiometabolic risk parallels Fads2 expression (high > wild-type > low), demonstrating a potent influence of Fads2 expression on metabolic phenotype.  However, dietary imbalance of n3:n6 PUFA intake, either toward higher n3 or n6 PUFA intake, tended to mitigate the effects of high and low Fads2 expression on glucose tolerance, indicating a supporting a complex interaction of Fads2 expression and essential PUFA intake on metabolic risk. Current studies in our lab are investigating the mechanisms of this interaction in hopes of elucidating relevant nutrigenetic criteria for developing individualized dietary recommendations to support optimal cardiometabolic health.