Lipid metabolism is tightly regulated by
nuclear receptors,
transcription factors, and cellular
enzymes. In this study, we demonstrated that the liver-enriched
transcription factor CREBH (cAMP-responsive
element binding protein, hepatocyte specific) and
peroxisome proliferator-activated receptor α (PPARα) function as binary transcriptional activators to regulate lipid metabolism by activating
fibroblast growth factor 21 (
FGF21), a hepatic
hormone that regulates whole-body energy homeostasis. Gain- and loss-of-function studies indicated that CREBH regulates
triglyceride and
fatty acid metabolism in animals under fasting or on an atherogenic high-fat (AHF) diet. CREBH and PPARα act as interactive
trans-activators that regulate each other for their expression. Activated CREBH
protein interacts with PPARα to form a functional complex upon fasting or the AHF diet, and both factors are required for induction of the metabolic
hormone FGF21. The CREBH-PPARα complex was found to bind to integrated CRE-
PPAR-responsive
element-binding motifs in the
FGF21 gene promoter. Whereas CREBH and PPARα function in synergy to activate
FGF21 gene expression, PPARα relies on CREBH to exert its trans-activation effect on
FGF21. Supporting the key role of CREBH in regulating
FGF21, infusion of recombinant
FGF21 protein can reverse
hypertriglyceridemia and hypoketonemia and partially rescue
nonalcoholic steatohepatitis developed in the CREBH-null mice after the AHF diet. Our study demonstrated a transcriptional regulatory axis of CREBH-PPARα-FGF21 in maintaining
lipid homeostasis under metabolic stress. The functional relationship between CREBH and PPARα in regulating
FGF21 may represent an important transcriptional coactivation mechanism that orchestrates the processes of energy supply upon metabolic alteration.