About Our Research

Generation of fat is an important mechanism for the body to store excess energy for future use. However, excess accumulation of fat, or deposition of fat in locations other than the adipose tissue, is associated with negative impact on health. Metabolic dysfunction-associated steatotic liver disease (MASLD, previously called NAFLD) is the most common liver disorder in the Western world, estimated to affect 25- 30% of Americans, and is becoming a leading cause of liver-related suffering and death. It is commonly associated with obesity, diabetes, elevated blood lipids and the metabolic syndrome. At its core, MASLD encompasses fat accumulation in the liver in response to excess nutrients, and in some patients also causes liver injury (steatohepatitis - MASH), which can lead to progression of liver disease. Interestingly, different individuals will accumulate different amounts of fat in their liver and not all individuals with MASLD will also develop the progressive form of MASH. The focus of our section is to understand this variability in the response to excess energy by studying mechanisms of fat accumulation in the liver, genetic influences, the natural history and progression to injury. Our ultimate goal is to use this knowledge to identify interventions to treat MASLD in individuals with the disorder and prevent it in those at risk.

Current Research

There are two main projects currently active in our section:

• From genetics to therapies: Through genetic studies we identified several genes that are implicated in the occurrence of MASLD and its progression. We are utilizing molecular biology techniques, animal models and human tissue and blood samples to dissect the mechanism by which these genes affect fat metabolism in the liver, as well as understand their normal physiological role. Our ultimate goal is to identify through these studies novel therapeutic targets for MASH.
• Food as a stress test: After a meal the liver is facing a surge of energy-rich nutrients. Inappropriate handling of this surge by the liver in people with MASLD may lead to the formation of toxic metabolites and drive the progression of MASH. As most clinical evaluations of people with MASLD are performed in the fasting state, the post-meal period remains relatively understudied. We are performing clinical and translational studies that aim to understand how the liver responds to a single meal, and how this response can lead to liver injury. We are collecting a wide range of samples from people with MASLD before and after a meal, including breath, blood, adipose tissue and liver, to assess the changes that occur in the tissue in the fed state. In addition, we are evaluating how this fasted-to-fed response can be used to predict the clinical response to treatment with semaglutide, a GLP-1 receptor agonist.

In addition, we have multiple projects utilizing the databases of the NIH Clinical Center and the biobanks established over the years by the Liver Diseases Branch to gain new insights into the pathogenesis of MASLD.