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.