Elevated Basal Expression of Liver Peroxisomal β-Oxidation Enzymes and CYP4A Microsomal Fatty Acid ω-Hydroxylase in STAT5b−/− Mice: Cross-Talk in Vivo between Peroxisome Proliferator-Activated Receptor and Signal Transducer and Activator of Transcription Signaling Pathways

Abstract

Long-term treatment of rodents with peroxisome proliferator chemicals, a group of structurally diverse nongenotoxic carcinogens, leads to liver cancer in a process dependent on the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα). Previous in vitro studies have shown that growth hormone (GH) can inhibit PPARα-dependent gene expression by down-regulation of PPARα expression and by a novel inhibitory cross-talk involving the GH-activated transcription factor STAT5b. Presently, we evaluate the role of STAT5b in mediating these inhibitory actions of GH on PPAR function using a STATb-deficient mouse model. Protein levels of three PPARα-responsive peroxisomal β-oxidation pathway enzymes (fatty acyl-CoA oxidase, 3-ketoacyl-CoA thiolase, and l-bifunctional enzyme) were increased up to two- to threefold in STAT5b−/− relative to wild-type control mouse liver, as was the basal expression of two PPARα-regulated cytochrome P450 4A proteins. In contrast, protein levels of two PPARα-unresponsive peroxisomal enzymes, catalase and urate oxidase, were not affected by the loss of STAT5b. A corresponding increase in expression of fatty acyl-CoA oxidase and l-bifunctional enzyme mRNA, as well as PPARα mRNA, was observed in the STAT5b-deficient mice, suggesting a transcriptional mechanism for the observed increases. Although basal liver expression of PPARα and its target genes was thus elevated in STAT5b−/− mice, the clofibrate-induced level of enzyme expression was unaffected, suggesting that the inhibitory effects of STAT5b are overcome at high concentrations of PPARα activators. These findings support the hypothesis that GH and potentially other endogenous activators of STAT5b help to maintain liver PPARα function at a low basal level and may thereby moderate PPARα-dependent hepatocarcinogenesis and other responses stimulated by exposure to low levels of environmental chemicals of the peroxisome proliferator class.