title: Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way.
abstract: The Constitutive Androstane Receptor (CAR, NR1I3) has been newly described as a regulator of energy metabolism. A relevant number of studies using animal models of obesity suggest that CAR activation could be beneficial on the metabolic balance. However, this remains controversial and the underlying mechanisms are still unknown. This work aimed to investigate the effect of CAR activation on hepatic energy metabolism during physiological conditions, i.e. in mouse models not subjected to metabolic/nutritional stress. Gene expression profiling in the liver of CAR knockout and control mice on chow diet and treated with a CAR agonist highlighted CAR-mediated up-regulations of lipogenic genes, concomitant with neutral lipid accumulation. A strong CAR-mediated up-regulation of the patatin-like phospholipase domain-containing protein 3 (Pnpla3) was demonstrated. Pnpla3 is a gene whose polymorphism is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) development. This observation was confirmed in human hepatocytes treated with the antiepileptic drug and CAR activator, phenobarbital and in immortalized human hepatocytes treated with CITCO. Studying the molecular mechanisms controlling Pnpla3 gene expression, we demonstrated that CAR does not act by a direct regulation of Pnpla3 transcription or via the Liver X Receptor but may rather involve the transcription factor Carbohydrate Responsive Element-binding protein. These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis. This also raises the question concerning the impact of drugs and environmental contaminants in lipid-associated metabolic diseases.
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Marmugi
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lukowicz
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lasserre
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Ducheix
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Goron
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Gamet-Payrastre
authors.affiliation: Institute of Regenerative Medicine and Biotherapy, INSERM, U1183 Montpellier, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gerbal-Chaloin
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pascussi
authors.affiliation: Centre de Recherche Saint-Antoine, INSERM, UMR 938, Sorbonne Universités, Université Paris 6, Paris, France; Institut Hospitalo-Universitaire ICAN, Paris, France.
authors.forename: Marthe
authors.initials: M
authors.lastname: Moldes
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pineau
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.affiliation: INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse, France; Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France. Electronic address: laila.lakhal@toulouse.inra.fr.
authors.forename: Laila
authors.initials: L
authors.lastname: Mselli-Lakhal
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000090702:Constitutive Androstane Receptor; D008049:Lipase; D000071518:Liver X Receptors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010634:Phenobarbital; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C506001:Mlxipl protein, mouse; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: Constitutive Androstane Receptor; Lipogenesis; Liver X Receptor; Non-alcoholic fatty liver disease; PNPLA3/adiponutrin