biostudies-literatureUnknownLee HKNIDDK NIH HHSGrowth hormone (GH) signaling through STAT5B is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5B^Y665F (gain-of-function) and STAT5B^Y665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5B^Y665F mice developed hepatic lipid accumulation, hypercholesterolemia, and enhanced insulin sensitivity, whereas STAT5B^Y665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5B^Y665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5B^Y665H failed to induce these pathways. Notably, STAT5B<supbioRxiv : the preprint server for biology2025.11.27.691004https://www.ebi.ac.uk/biostudies/studies/S-EPMC12694592biostudies-literatureDisease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism.PMC12694592R01 DK121998Hennighausen LWaxman DJPyatkov MLiu NYe BDemby TLee HKFurth PAGavrilova OfalseDisease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism.Growth hormone (GH) signaling through STAT5B is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5B^Y665F (gain-of-function) and STAT5B^Y665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5B^Y665F mice developed hepatic lipid accumulation, hypercholesterolemia, and enhanced insulin sensitivity, whereas STAT5B^Y665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5B^Y665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5B^Y665H failed to induce these pathways. Notably, STAT5B<sup2025-01-01T00:00:00Z2025 Dec2026-06-04T03:20:58.73Z2026-06-04T03:12:38.467ZS-EPMC126945924138377910.1101/2025.11.27.691004