title: Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes.
abstract: OBJECTIVE
  The adiponutrin/PNPLA3 (patatin-like phospholipase domain-containing protein 3) variant I148M has recently emerged as an important marker of human fatty liver disease. In order to understand the role of the adiponutrin/PNPLA3 protein, we investigated the regulation of its expression in both human and mouse hepatocytes.
  
  
  METHODS
  Adiponutrin/PNPLA3 and lipogenic enzyme expression was determined by real-time PCR analysis in a wide panel of analysis in vivo in the mouse liver and in vitro in murine hepatocytes and human hepatocyte cell lines infected with ChREBP or SREBP1c-expressing adenoviruses.
  
  
  RESULTS
  We show that in the mouse liver, adiponutrin/PNPLA3 gene expression is under the direct transcriptional control of ChREBP (carbohydrate-response element-binding protein) and SREBP1c (sterol regulatory element binding protein1c) in response to glucose and insulin, respectively. In silico analysis revealed the presence of a ChoRE (carbohydrate response element) and of a SRE (sterol response element) binding site on the mouse adiponutrin/PNPLA3 gene promoter. Point mutation analysis in reporter gene assays identified the functional response of these two binding sites in the mouse adiponutrin/PNPLA3 promoter. In contrast, in human immortalized hepatocytes and in HepG2 hepatoma cells, only SREBP1c was able to induce adiponutrin/PNPLA3 expression, whereas ChREBP was unable to modulate its expression.
  
  
  CONCLUSIONS
  All together, our results suggest that adiponutrin/PNPLA3 is regulated by two key factors of the glycolytic and lipogenic pathways, raising the question of its implication in the metabolism of carbohydrates and lipids.
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Dubuquoy
authors.forename: Céline
authors.initials: C
authors.lastname: Robichon
authors.forename: Françoise
authors.initials: F
authors.lastname: Lasnier
authors.forename: Clotilde
authors.initials: C
authors.lastname: Langlois
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dugail
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Burnol
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.forename: Marthe
authors.initials: M
authors.lastname: Moldes
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008049:Lipase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009687:Nuclear Proteins / Q000378:metabolism*; D009752:Nutritional Status; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005947:Glucose; D007328:Insulin; D008049:Lipase; D008565:Membrane Proteins; D009687:Nuclear Proteins; D054512:Phospholipases A2, Calcium-Independent; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C549791:PNPLA3 protein, mouse; D000217:Acyltransferases; C533682:PNPLA3 protein, human