To elucidate the physiological role of CREBH, the hepatic mRNA and protein levels of CREBH were estimated in various feeding states of wild and obesity mice. In the fast state, the expression of CREBH mRNA and nuclear protein were high and profoundly suppressed by refeeding in the wild-type mice. In ob/ob mice, the refeeding suppression was impaired. The diet studies suggested that CREBH expression was activated by fatty acids. CREBH mRNA levels in the mouse primary hepatocytes were elevated by addition of the palmitate, oleate and eicosapenonate. it was also induced by PPAR alpha agonist and repressed by PPAR alpha antagonist. Luciferase reporter gene assays indicated that the CREBH promoter activity was induced by fatty acids and co-expression of PPAR alpha. Deletion studies identified the PPRE for PPAR alpha activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) assay confirmed that PPAR alpha directly binds to the PPRE. Activation of CREBH at fasting through fatty acids and PPAR alpha suggest that CREBH is involved in nutritional regulation. (C) 2009 Elsevier Inc. All rights reserved.