Stephanie Marshall
Matriculation Year: 2008
Department: Pathology - Lipid Sciences
Education:
- BS (2008) Food Science, and BA (2008) Chemistry, North Carolina State University.
Research Interests:
My current research projects focus on the metabolic syndrome, specifically hepatosteatosis and cholesterol metabolism. Hepatosteatosis is the most prevalent liver abnormality in developed nations and is important in many disease processes such as diabetes and atherosclerotic cardiovascular disease (ASCVD). It currently lacks a known treatment option. One of the projects I am currently researching is cholesteryl ester’s (CE) role in promoting hepatic triglyceride accumulation. This project has required animal and cell culture skills to determine to what extent dietary cholesterol promotes hepatic TG accumulation.
I employed drug treatments to test whether blocking CE accumulation in the liver could prevent further hepatic TG accumulation. An interesting phenomenon that I discovered when I blocked hepatic cholesterol esterification, was that cholesterol is rapidly cleared from the murine liver while hepatic TG is more resistant to mobilization. The striking cholesterol results from these studies lead me to investigate cholesterol metabolism. Recently, I have been studying the non-biliary cholesterol excretion pathway. Our group has shown that when hepatic cholesterol cannot be esterified it is rapidly cleared from the body. Interestingly, the hepatic loss of cholesterol is not readily found in the bile, the classical mode of cholesterol excretion. This lead us to hypothesize that there must be a non-biliary excretion pathway.
My role in studying this pathway is investigating the mode of delivery for cholesterol from the liver directly to the intestine. We hypothesize that hepatic apolipoprotein B (apoB) containing particles are responsible for transintestinal cholesterol excretion. In order to study this hypothesis I have utilized pharmaceuticals to knockdown hepatic microsomal triglyceride transfer protein (MTP), an integral component of apoB lipidation and stabilization. Thus limiting the activity of hepatic MTP reduces hepatic very low density lipoprotein (VLDL) secretion. Reduction of MTP activity has minimal effect on bile cholesterol levels yet reduces fecal neutral cholesterol loss (FNSL), a key readout in cholesterol secretion. Intriguingly reducing hepatic VLDL secretion reduces FNSL without a reduction in biliary cholesterol and therefore supports that apoB containing particles are integral to the non-biliary cholesterol excretion pathway.
These results can mean advancement in ASCVD treatment. Currently statins are the best treatment modality for lowering total plasma cholesterol levels. Even with this remarkable drug CVD is still the leading cause of health related deaths in America. Discovering a novel treatment modality to increase cholesterol excretion could enhance the beneficial effects of statins. It is well known that the biliary cholesterol excretion pathway can be overwhelmed and negatively result in gallstones. Enhancing the non-biliary pathway is a novel treatment area that is yet to be fully explored.
Publications: