title: Cannabinoid receptor type 1 (CB1R) signaling regulates hepatic gluconeogenesis via induction of endoplasmic reticulum-bound transcription factor cAMP-responsive element-binding protein H (CREBH) in primary hepatocytes.
abstract: Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with fatty liver, insulin resistance, and impaired suppression of hepatic glucose output. Endoplasmic reticulum stress-associated liver-specific transcription factor CREBH is emerging as a critical player in various hepatic metabolic pathways and regulates hepatic gluconeogenesis in diet-induced obese settings. In this study, we elucidated the critical role of CREBH in mediating CB1R signaling to regulate glucose homeostasis in primary rat and human hepatocytes. mRNA and protein levels and glucose production were analyzed in primary rat and human hepatocytes. ChIP assays were performed together with various transcriptional analyses using standard techniques. CB1R activation by 2-arachidonoylglycerol (2-AG) specifically induced CREBH gene expression via phosphorylation of the JNK signaling pathway and c-Jun binding to the AP-1 binding site in the CREBH gene promoter. 2-AG treatment significantly induced hepatic gluconeogenic gene expression and glucose production in primary hepatocytes, and we demonstrated that the CREBH binding site mutant significantly attenuated 2-AG-mediated activation of the gluconeogenic gene promoter. Endogenous knockdown of CREBH led to ablation of 2-AG-induced gluconeogenic gene expression and glucose production, and the CB1R antagonist AM251 or insulin exhibited repression of CREBH gene induction and subsequently inhibited gluconeogenesis in both rat and human primary hepatocytes. These results demonstrate a novel mechanism of action of activated CB1R signaling to induce hepatic gluconeogenesis via direct activation of CREBH, thereby contributing to a better understanding of the endocannabinoid signaling mechanism involved in regulating the hepatic glucose metabolism.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chanda
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D063388:Endocannabinoids; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis / Q000235:genetics; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1
chemical_list: D001095:Arachidonic Acids; C571130:CNR1 protein, human; C533813:CREB3L3 protein, human; D063385:Cannabinoid Receptor Modulators; D017362:Cyclic AMP Response Element-Binding Protein; D063388:Endocannabinoids; D005989:Glycerides; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D018808:Transcription Factor AP-1; C094503:glyceryl 2-arachidonate; D048670:MAP Kinase Kinase 4; D005947:Glucose