Disease-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^Y665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5B^Y665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5B^Y665H. Beyond the liver, STAT5B^Y665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5B^Y665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.