The growth hormone (GH)-responsive cytochrome P450 (CYP) 2C11 is down-regulated in vitamin A-deficient (VAD) rat liver. This study assessed the impact of a VAD diet on the hepatic Janus kinase-Signal Transducers and Activators of Transcription (JAK-STAT) system that mediates GH signalling. Nuclear tyrosine- and serine-phosphorylated STAT5 accumulated in VAD liver, whereas nuclear JAK2 tyrosine kinase and SHP-1 phosphatase were decreased. Tyrosine-phosphorylated SHP-1 was decreased to 36+/-14% of control (P<0.01), indicating its impaired activation in VAD liver. Episodic GH pulses increased nuclear phospho-STAT5, especially in control liver, but nuclear phospho-JAK2 and phospho-SHP-1 were not restored. CYP2C11 protein and testosterone 16alpha-hydroxylation were decreased in VAD liver to 67+/-16% and 76+/-19% of control, and were further decreased by GH to 32+/-8% and 30+/-14% of control. Thus, hypo-responsiveness of JAK-STAT in VAD liver is associated with impaired nuclear phospho-STAT dephosphorylation.
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