title: Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21.
abstract: 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.
authors.affiliation: Center for Molecular Medicine and Genetics (H.K., R.M., Z.Z., J.C., R.Z., K.Z.), Department of Immunology and Microbiology (K.Z.), The Wayne State University School of Medicine, Detroit, Michigan 48201; and Cardiovascular Center (L.C.), Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Hyunbae
authors.initials: H
authors.lastname: Kim
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendez
authors.forename: Ze
authors.initials: Z
authors.lastname: Zheng
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
authors.forename: Juan
authors.initials: J
authors.lastname: Cai
authors.forename: Ren
authors.initials: R
authors.lastname: Zhang
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D006706:Homeostasis; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D047493:PPAR alpha / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D012689:Sequence Homology, Nucleic Acid; D014280:Triglycerides / Q000378:metabolism
chemical_list: C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005227:Fatty Acids; D008055:Lipids; D047493:PPAR alpha; D011994:Recombinant Proteins; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors