Gys-2 was identified to be a PPARα target gene since PPARα ligands induced Gys-2 expression in rat and mouse primary hepatocytes but not in PPARα −/− hepatocytes [44]. Two putative PPREs were identified in the mouse Gys-2 gene. Based on chromatin immunoprecipitation (ChIP) analysis, gel-shift experiments and luciferase reporter assays, the direct repeat 1 (DR1) in intron 1 (DR1int) was shown to be the response element for PPARs and the DR1 in the upstream promoter (DR1prom) the response element for hepatocyte nuclear factor 4 alpha (HNF4α). In liver, which expresses high amounts of HNF4α, DR1prom is occupied and activated by HNF4α, but not by PPARα, while DR1int is bound by PPARα and not by HNF4α [44]. It was suggested that during fasting, when hepatic PPARα levels increase, competition between these two transcription factors may take place at the level of binding to common co-activator proteins [44]. Taken together, these in vitro observations indicate that besides HNF4α, PPARα activation might promote Gys-2 expression. For GP, the key enzyme of glycogen breakdown, there are no in vitro studies on regulation by PPARα so far.
