Coronary artery disease (CAD) remains a leading cause of premature death in the Western world. New approaches are therefore required to reduce circulating levels of low-density lipoprotein (LDL)-cholesterol, which is a major risk factor for the disease. For many years, it was assumed that the majority of excess cholesterol is eliminated from the body via the hepatobiliary route. However, it has been discovered recently that up to 35% of excreted cholesterol is delivered directly to the intestinal lumen by shuttling LDL particles through enterocytes in a process termed trans-intestinal cholesterol efflux (TICE).
Our recent studies suggest that dietary consumption of molecules that stimulate pattern-recognition receptors (PRRs) of the innate immune system (called pathogen-associated molecular patterns, or PAMPs) results in increased levels of LDL-C in human volunteers. This project will test the hypothesis that PRR-signalling may also result in reduced TICE flux in enterocytes, thereby leading to elevated serum LDL-C.
The project will seek to address the following major questions:
1. Which PAMPs are capable of stimulating PRR-signalling in enterocytes of the small intestine? 2. How does PRR-signalling connect to transcriptional regulators of major TICE mediators? 3. Does PRR-signalling regulate cholesterol efflux from enterocytes?
The methods used in this project will include in vitro mammalian cell culture, transwell systems, ELISA, qPCR, Western blot, fluorescence microscopy and radiolabel/scintillation assays.
The expected outcome is an improved understanding of the mechanisms connecting PRR-signalling to cholesterol metabolism in enterocytes, which may point the way towards novel drug targets for LDL-C lowering.
This project is self-funded. Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website (View Website) as they become available.