Thursday, May 15, 2025
5/15/2025
The Effect of Alcohol and High Fat Diet on Kupffer Cell Function - PROJECT SUMMARY Alcohol- and obesity-related liver disease are the leading cause for liver transplant in the United States. Steatohepatitis describes a state of liver inflammation and lipid accumulation that is seen in both disease states. Uniquely, patients with alcohol-related liver disease can suffer from a state of acute on chronic liver failure known as “alcoholic hepatitis”. The reasons for why a similar phenomenon is not present in obesity- related fatty liver disease is not understood. We have been able to replicate a liver failure-like state seen in human “alcoholic hepatitis” by ablating mature Kupffer Cells in a mouse model fed a high fat and alcohol diet. We have also shown that over an extended course, mouse fed a high fat diet with alcohol spontaneously lose embryonically derived Kupffer Cells leading to a paucity of mature KCs. In obesity-related steatohepatitis models, embryonic Kupffer Cells are similarly lost, but these are replaced by maturing monocyte-derived KCs so there is no net loss of mature Kupffer Cell function. Thus, our hypothesis is that mature Kupffer Cells are depleted during alcohol conditions and although they are replaced, their replacement populations are unable to fully transition towards this mature state, leading to a loss of homeostasis and providing a platform for worsening disease states including “alcoholic hepatitis”. We will test this hypothesis with 2 specific aims. Aim 1 will fate map liver macrophages using a lineage tracer mouse model to define their embryological origin and create an identifying signature that we will use to examine human models of alcohol- and obesity-related liver disease. Aim 2 will evaluate the assess these macrophage subsets ex vivo and use co-culture systems and exosome isolation techniques to determine how these macrophages effect hepatocyte function. We anticipate that 1) monocyte derived macrophages from our alcohol model will display some similarities to the transcriptome of embryonic Kupffer cells but will lack specific markers of full maturation and tolerogenic signals and 2) this subset will this be more inflammatory and unable to maintain a homeostatic environment when challenged in co-culture environments. The findings of this study will help us further define the pathogenesis of alcohol-related liver disease and provide information on new targetable pathways for treatment. As a clinical gastroenterology fellow in the physician scientist training pathway, my goal is to become a successful independent investigator leading a research team focused on elucidating immunological pathways within the gut-liver axis as it relates to health and disease. The research training plan addresses gaps in my research experience by reinforcing technical and theoretical skills I have previously developed, while also driving my research skillset forward by learning new techniques in a closely mentored environment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).