title: Hepatic nutrient and hormonal regulation of the PANcreatic-DERived factor (PANDER) promoter.
abstract: PANcreatic-DERived factor (PANDER, FAM3B) has been shown to regulate glycemic levels via interactions with both pancreatic islets and the liver. Although PANDER is predominantly expressed from the endocrine pancreas, recent work has provided sufficient evidence that the liver may also be an additional tissue source of PANDER production. At physiological levels, PANDER is capable of disrupting insulin signaling and promoting increased hepatic glucose production. As shown in some animal models, strong expression of PANDER, induced by viral delivery within the liver, induces hepatic steatosis. However, no studies to date have explicitly characterized the transcriptional regulation of PANDER from the liver. Therefore, our investigation elucidated the nutrient and hormonal regulation of the hepatic PANDER promoter. Initial RNA-ligated rapid amplification of cDNA ends identified a novel transcription start site (TSS) approximately 26 bp upstream of the PANDER translational start codon not previously revealed in pancreatic β-cell lines. Western evaluation of various murine tissues demonstrated robust expression in the liver and brain. Promoter analysis identified strong tissue-specific activity of the PANDER promoter in both human and murine liver-derived cell lines. The minimal element responsible for maximal promoter activity within hepatic cell lines was located between -293 and -3 of the identified TSS. PANDER promoter activity was inhibited by both insulin and palmitate, whereas glucose strongly increased expression. The minimal element was responsible for maximal glucose-responsive and basal activity. Co-transfection reporter assays, chromatin-immunoprecipitation (ChIP) and site-directed mutagenesis revealed that the carbohydrate-responsive element binding protein (ChREBP) increased PANDER promoter activity and interacted with the PANDER promoter. E-box 3 was shown to be critical for basal and glucose responsive expression. In summary, in-vitro and in-vivo glucose is a potent stimulator of the PANDER promoter within the liver and this response may be facilitated by ChREBP.
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA.
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Ratliff
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Athanason
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA.
authors.forename: Alicia C
authors.initials: AC
authors.lastname: Chechele
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA.
authors.forename: Melanie N
authors.initials: MN
authors.lastname: Kuehl
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Fernandez
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: MarElia
authors.affiliation: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA. Electronic address: bburkhardt@usf.edu.
authors.forename: Brant R
authors.initials: BR
authors.lastname: Burkhardt
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D016207:Cytokines; C577825:FAM3B protein, human; D007328:Insulin; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C504749:PANDER protein, mouse; D014157:Transcription Factors; D005947:Glucose
keywords: ChREBP; Fam3B; Glucose; Liver; PANDER; Transcription