Elucidating the role of ketone bodies in hepatic pufa homeostasis and masld-mash progression

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the Regents of the University of Minnesota $107,925 on September 13, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct research elucidating the role of ketone bodies in hepatic polyunsaturated fatty acid homeostasis and metabolic dysfunction-associated steatotic liver disease and steatohepatitis progression.

The research investigates whether ketogenesis-derived carbon sources direct malonyl-CoA to hepatic polyunsaturated fatty acid elongation via acetoacetyl-CoA synthetase, which protects against liver disease by suppressing de novo lipogenesis. The project employs subcellular fractionation and mass spectrometry-driven proteomics combined with stable isotope tracing to study the co-localization of acetoacetyl-CoA synthetase and polyunsaturated fatty acid elongation enzymes within peri-lipid droplet mitochondria-associated membranes. A second objective tests the hypothesis that ketone-sourced polyunsaturated fatty acids protect against liver injury and inflammation using three loss-of-function mouse models lacking key ketone body metabolic enzymes and physiological and analytical methodologies to quantify indices of liver metabolism and injury.

Performance of research is located in Minneapolis, Minnesota. The period of performance extends from the award date through May 31, 2028.

Abstract

This project is fueled by candidate's ambitions to build an independent academic research program at the intersection of biochemistry, physiology, and analytical chemistry, that explores intermediary lipid metabolism and shifts in subcellular lipid pools, to understand the molecular origins of metabolic diseases. This training project focuses on metabolic dysfunction-associated steatotic liver disease (masld) and steatohepatitis (mash) which are the leading cause of liver disease in western countries. Due to complex systemic and liver- autonomous factors influencing masld-mash development and progression, treatment options are scarce, triggering an urgent need to better understand the molecular origins to develop new drug targets. The primary objective of this project is to investigate the role of ketone body-sourced polyunsaturated fatty acids (pufas) in the development of masld-mash, implicating ketogenesis as a potential therapeutic target. This project will test the central hypothesis that ketogenesis-derived carbon sources malonyl-COA to hepatic pufa elongation, via acetoacetyl-COA synthetase (aacs), which protects against masld-mash by suppressing absolute rates of hepatic DE novo lipogenesis. In aim 1, a convergence of subcellular fractionation and mass spectrometry (MS)-driven proteomics and stable isotope tracing will be leveraged to study the CO-localization of aacs and pufa elongation enzymes within peri-lipid droplet mitochondria-associated membranes. In aim 2, the hypothesis that ketone-sourced pufas protect against liver injury and inflammation will be tested using three loss-of-function mouse models, that strategically lack key ketone body metabolic enzymes, and a suite of physiological and analytical methodologies to quantify indices of liver metabolism and injury. These findings will deepen our understanding of the link between ketogenesis, pufas, and liver injury, and in so doing, implicate interventions such as intermittent fasting or low-carbohydrate diets that provoke ketosis as therapeutic options during masld-mash. This project will take place in the division of molecular medicine at the university of minnesota medical school. Molecular medicine houses multiple labs focused on leveraging cutting-edge analytical tools to acquire high resolution molecular and phenotypical profiles, to better understand the metabolic underpinnings of human diseases. In this environment, and in conjunction with my CO-sponsors, collaborators, and consultants, the outlined training plan will (1) provide proficiencies in subcellular fractionation, proteomics, and specialized training in shotgun lipidomics, and (2) provide experiences leveraging these tools to study in vivo diseases using dietary and genetic mouse models. Collectively, this will generate a unique and highly personalized training experience to prepare for a career focused on studying the molecular origins of metabolic diseases.