Bud13 Constrains Diet-Responsive Hepatic Transcriptional Plasticity and Susceptibility to Metabolic Dysfunction
Metabolic dysfunction associated steatotic liver disease (MASLD) is a major hepatic complication of obesity, yet the mechanisms linking genetic susceptibility to hepatic metabolic dysregulation remain incompletely understood. Genome-wide association studies have implicated BUD13 as a risk locus for metabolic traits, but its physiological role in the liver is unclear. Here, we examined the in vivo function of Bud13 using CRISPR/Cas9-generated Bud13-deficient mice. Bud13 haploinsufficiency increased susceptibility to diet-induced metabolic stress, leading to exacerbated obesity, hepatic steatosis and insulin resistance under high-fat diet conditions. Transcriptomic analyses demonstrated that reduced Bud13 activity reshaped diet-responsive hepatic gene expression programs, altering both the magnitude and direction of transcriptional responses in specific gene subsets. Bud13 haploinsufficiency was also associated with changes in intron retention in selected metabolically responsive transcripts, suggesting a contributory role for RNA processing in hepatic transcriptional reprogramming. Collectively, these findings identify Bud13 as a modulator of hepatic metabolic adaptation to nutrient excess and provide insight into how a genetic risk factor may influence susceptibility to MASLD.