Abstract

Obesity and type 2 diabetes are leading causes of a serious liver disease called metabolic dysfunction-associated steatohepatitis (MASH), in which the liver becomes inflamed and scarred, eventually leading to liver failure. Despite its growing prevalence, few effective treatments exist. This project investigates how immune cells in the liver contribute to this condition and whether targeting their cholesterol handling could offer a new treatment approach.

The liver contains specialized immune cells called Kupffer cells, which help maintain organ health by clearing fats and cholesterol from the bloodstream. In people with obesity and diabetes, these cells become overwhelmed by excess fat and cholesterol, triggering chronic inflammation that damages the liver over time. Understanding what drives this harmful immune response is critical for developing better therapies.

This research focuses on a family of proteins called Asters, which control how cholesterol moves within cells. Preliminary evidence suggests that blocking one of these proteins protects mice from developing severe fatty liver disease by reducing cholesterol buildup and inflammation. Aster proteins are particularly abundant in liver immune cells and become more active under the metabolic stress seen in diabetes and obesity.

This Fellowship will determine how Aster proteins regulate cholesterol movement in Kupffer cells and how this influences liver inflammation and scarring in animal models of metabolic disease. By uncovering how cholesterol handling in immune cells drives liver damage, this work aims to identify new drug targets for treating MASH in patients with type 2 diabetes and obesity.