Federal Grant Award Summary

The University of Pennsylvania received a $892,491 Project Grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847), effective February 1, 2026 through December 31, 2029. The award funds research investigating acetyl-CoA (acetyl-coenzyme A) metabolism and its role in regulating hepatic lipid homeostasis in metabolic dysfunction-associated steatotic liver disease (MASLD). The research applies advanced analytical techniques including spatio-temporal lipidomics, metabolic flux analysis, and gene expression analysis to elucidate how the enzyme ATP-citrate lyase (ACLY) regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent gene expression and lipid metabolism in response to dietary stimuli.

The project delivers two primary research objectives: first, examining ACLY's role in mediating diet-dependent lipid metabolism and its effects on PPARα signaling pathways; and second, characterizing the ACLY-independent functions of bempedoic acid, an FDA-approved cholesterol therapeutic, to understand how this drug reshapes hepatic metabolism and circadian PPARα signaling. The research leverages genetic mouse models and in vivo stable isotope tracing methodologies to generate fundamental mechanistic insights intended to inform the development of more effective acetyl-CoA metabolism inhibitors for treating MASLD and related metabolic diseases.