PROJECT SUMMARY/ABSTRACT
The overall objective of this research is to target hepatocyte lipid droplets (LDs) for the development of
therapeutic interventions for fatty liver disease. Hepatic steatosis, fat accumulation within hepatocyte LDs, is a key
precursor for steatohepatitis which can lead to cirrhosis and hepatocellular cancer, necessitating liver
transplantation. Unfortunately, hepatic steatosis also limits the number of donor livers acceptable for transplant as
donor livers with severe steatosis have a high risk of primary nonfunction. As such, therapeutic strategies to
reverse fatty liver are important for patients at risk for steatohepatitis and cirrhosis as well as to increase the
donor pool of viable livers for transplantation. Our work focused on hepatocyte LDs herein shows three key
observations: a) perilipin-2 (PLIN2), a LD-associated protein which regulates fat storage and utilization, co-
localizes with and co-immunoprecipitates microtubules; b) microtubule disruption with nocodazole, a blunt
microtubule targeting agent (MTA), uncouples PLIN2 from the LD, promotes LD fusion and yields delipidation (i.e.
exocytotic secretion of LD contents) of steatotic hepatocytes with minimal cytotoxicity; and c) nocodazole
promotes fat loss from ex vivo liver tissue with no effect on tissue viability. Based on these preliminary data, we
propose the CENTRAL HYPOTHESIS that hepatocyte LDs are regulated by an interaction between PLIN2 and
the microtubule cytoskeleton, and that this interaction is a potential therapeutic target to decrease the lipid burden of
hepatocytes in fatty liver disease. Our SPECIFIC AIMS will test three hypotheses. FIRST, we will test the
hypothesis that microtubules directly interact with LD-associated PLIN2. SECOND, we will test the hypothesis
that microtubule perturbation increases lipolysis and leads to delipidation of steatotic hepatocytes. FINALLY, we
will test the hypothesis that treatment of ex vivo steatotic liver tissue and ex vivo perfusion of steatotic livers with
MTAs will lead to delipidation of hepatocytes and improved liver function in a pre-clinical model of organ salvage
and rehabilitation. This work will provide foundational information to the emerging field of LD biology and is
projected to demonstrate a novel cellular mechanism controlling hepatocyte LD dynamics and to identify
therapeutic strategies to defat steatotic livers. The candidate is a basic scientist and transplant hepatologist,
dedicated to improving the lives of patients with liver disease using a basic science approach. She is an Assistant
Professor of Medicine at Mayo Clinic with a mentorship team consisting of Drs. Vijay Shah and Greg Gores. She has
protected time for research and training activities, dedicated institutional funding for equipment and supplies, and
a robust career development plan with specific activities and benchmarks that will position her for an
independent research career. The comprehensive training plan will allow for the candidate to complete her
current research plan and seek independent investigator status where she will translate these and future studies
to human trials and future therapeutic interventions for patients.
