Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism.

ABSTRACT: 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

SUBMITTER: Lee HK 

PROVIDER: S-EPMC12694592 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature