How does diet improve metabolic health? Dissecting bioenergetic pathways altered by diet using genomic approaches (TRAKA_F17DTP1)

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Broccoli-rich diets have been associated with reduced risk of developing a range of chronic diseases, such as cardiovascular disease and certain cancers. We have recently showed that consumption of broccoli rich diets reduces LDL cholesterol and fasted glucose levels, which suggests that broccoli modulates central metabolic pathways in a manner that may protect against development of chronic diseases. Broccoli is rich in glucoraphanin, a sulphur-containing glucoside that though not bioactive itself is readily metabolised in the gut to bioactive sulforaphane. By using cell and animal models sulforaphane has been linked to the activation of a key transcription factor, nuclear factor-erythroid 2 like 2 (NRF2), which is responsible for upregulating a host of antioxidant genes by binding to a defined element within their promoter. Recent evidence suggests that NRF2 may also play a role in modulating energy metabolism that though under-explored is likely the mechanism by which broccoli-rich diets promote good health. This PhD project will focus on studying the importance of NRF2 activation in mediating the changes in liver metabolic pathways that can maintain health. This project will, first, use whole genome sequencing techniques to identify the transcriptional cascades that are altered by broccoli bioactives and NRF2 and understand their effect on fatty acid metabolism and cellular bioenergetics. There will also be opportunity to engineer novel genetic knockout human cells through genome editing to specifically understand the importance of nrf2 in mediating metabolic regulation by dietary bioactives.