Evidence for the role of delta-6-desaturase in the development of cardiometabolic disease
Mulligan, Christopher Myles, author
Chicco, Adam J., advisor
Harris, Mary, committee member
Frye, Melinda, committee member
Vanamala, Jairam, committee member
The following investigation comprises a series of experiments with the overall aim of elucidating the role of delta-6-desaturase (D6D) in the development of cardiometabolic disease. The experiments tested the general hypothesis that changes in fatty acid membrane composition found to be associated with cardiometabolic disease are attributed to delta-6-desaturase activity and contribute to the development of disease. The specific aims of each experimental series were to: 1) Determine whether inhibition of D6D in vivo in established models of heart failure and type 2 diabetes (T2D) reverses changes in fatty acid membrane composition associated with disease pathogenesis and attenuates associated cardiometabolic insults, and 2) Determine whether over-expression of fads2, the gene that encodes for D6D, results in altered membrane fatty acid composition and the development of metabolic insults associated with (T2D). Studies in aim 1 demonstrated that the changes in fatty acid membrane composition observed in heart failure and T2D/insulin resistance are a result of increased metabolism of polyunsaturated fatty acids (PUFAs) through D6D, the rate limiting enzyme in the PUFA metabolism pathway. Pharmacological inhibition of D6D with SC-26196 reversed the aberrant fatty acid membrane composition, reduced myocardial hypertrophy and preserved contractile function in the rodent model of heart failure, and improved glucose tolerance in the rodent model of T2D/insulin resistance. Studies in aim 2 demonstrated D6D as not only a contributor to metabolic disease but a key driver of its development. The animal model of genetic fads2 over-expression, the gene that encodes for D6D, develops significant glucose and insulin intolerance with age and has significantly elevated blood lipid levels. Collectively, these findings provide substantial evidence for the role of D6D in phospholipid fatty acid membrane composition and the development and progression of cardiometabolic disease.