title: Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism.
abstract: Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Hyunbae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendez
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Xuequn
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan, USA kzhang@med.wayne.edu.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005215:Fasting / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005934:Glucagon / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics* / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D047495:PPAR gamma / Q000378:metabolism; D017434:Protein Structure, Tertiary; D056564:Sirtuin 1 / Q000378:metabolism; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005934:Glucagon; D051548:Histone Acetyltransferases; D047495:PPAR gamma; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C500051:Creb3l3 protein, mouse; C470545:Sirt1 protein, mouse