My research concerns the mechanisms by which nuclear receptors, specifically the liver X receptor (LXR), balance metabolic and inflammatory responses during the course of chronic liver injury. All forms of chronic liver disease (e.g. fatty liver, viral hepatitis, alcoholism) lead to a stereotyped wound healing response-fibrosis-that is mediated by a sub-population of liver cells known as hepatic stellate cells. These cells store 80% of the body's supply of retinoids (Vitamin A and its metabolites) but the function of retinoids in stellate cells is largely unknown. To this end, I have spent the last two years of my PhD training program with Dr. Peter Tontonoz at UCLA studying the role of cholesterol and fatty acid metabolism in hepatic stellate cells. We have discovered that global deletion of LXRs renders mice susceptible to liver fibrosis in at least two forms of liver injury. Furthermore, stellate cells from LXR null mice have a diminished pool of retinoids that correlates with a pro-inflammatory, pro-fibrotic phenotype. This suggests that cholesterol and fatty acid metabolism are important for maintaining hepatic stellate cells in a quiescent state.
In Aim 1 of this proposal, we will determine the relative contribution that stellate cells make to the susceptibility of LXR null animals to develop fibrosis.
Aim 2 tests the hypothesis that anti-inflammatory properties of LXRs help maintain stellate cells in a quiescent state.
This aim will also test whether LXRs regulate stellate cell proliferation.
Aim 3 tests the role of LXRs in the storage of vitamin A in stellate cells and the crosstalk between cholesterol, fatty acids, and retinoid metabolism. The results of these studies will define the importance of LXRs for normal stellate cell function and response to chronic liver injury. The additional training and expertise I will acquire and the data generated in the 5-year award period is expected to open up new avenues for research in stellate cell biology. It will also provide sufficient publications and data to establish myself as an independent investigator, capable of competing for R01 level funding from the NIH.
The research proposed here is designed to understand the relevance of metabolism to the development of liver scarring (fibrosis) that occurs in common, chronic diseases (e.g. fatty liver and diabetes, alcoholism, and viral hepatitis B and C). We are studying the body's natural cholesterol sensor, the liver X receptor (LXR), to see how it affects the activity of the specific cell in the liver that causes liver scarring to occur. This research is relevant to public health because it has the potential to identify novel targets for treating multiple types of liver diseases for which there are currently no good medical therapies.
