Cross-talk between Janus kinase-signal transducer and activator of transcription (JAK-STAT) and peroxisome proliferator-activated receptor-α (PPARα) signaling pathways -: Growth hormone inhibition of PPARα transcriptional activity mediated by STAT5b

Hepatic peroxisome proliferation induced by structurally diverse non-genotoxic carcinogens is mediated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR alpha) and can be inhibited by growth hormone (GH), GH-stimulated Janus kinase-signal transducer and activator of transcription 5b (JAK2/ STAT5b) signaling and the PPAR activation pathway were reconstituted in COS-1 cells to investigate the mechanism for this GH inhibitory effect. Activation of STAT5b signaling by either GH or prolactin inhibited, by up to 80-85%, ligand-induced, PPAR alpha-dependent reporter on. GH failed to inhibit 15-deoxy-Delta(12,14)-prostaglandin-J(2)-stimulated gene transcription mediated by an endogenous COS-1 PPAR-related receptor, GH inhibition of PPAR alpha activity required GH receptor and STAT5b and was not observed using GH-activated STAT1 in place of STAT5b, GH inhibition was not blocked by the mitogen-activated protein kinase pathway inhibitor PD98059, STAT5b-PPAR alpha protein-protein interactions could not be detected by anti-STAT5b supershift analysis of PPAR alpha-DNA complexes. The GH inhibitory effect required the tyrosine phosphorylation site (Tyr-699) of STAT5b, an intact STAT5b DNA binding domain, and the presence of a COOH-terminal transactivation domain. Moreover, GH inhibition was reversed by a COOH-terminal-truncated, dominant-negative STAT5b mutant. STAT5b must thus be nuclear and transcriptionally active to mediate GH inhibition of PPAR alpha activity, suggesting an indirect inhibition mechanism, such as competition for an essential PPAR alpha co-activator or STAT5b-dependent synthesis of a more proximal PPARa inhibitor. The cross-talk between STAT5b and PPAR alpha signaling pathways established by these findings provides new insight into the mechanisms of hormonal and cytokine regulation of hepatic peroxisome proliferation.