Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way

Journal Article · Fri Jul 15 00:00:00 EDT 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.05.006· OSTI ID:22689203

Marmugi, Alice; Lukowicz, Céline; Lasserre, Frederic; Montagner, Alexandra; Polizzi, Arnaud; Ducheix, Simon; Goron, Adeline; Gamet-Payrastre, Laurence ^[1]; Gerbal-Chaloin, Sabine ^[2]; Pascussi, Jean Marc ^[3]; Moldes, Marthe ^[4]; Pineau, Thierry; Guillou, Hervé ^[1]; Mselli-Lakhal, Laila ^[1]

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1. INRA, TOXALIM (Research Centre in Food Toxicology), Toulouse (France)
2. Institute of Regenerative Medicine and Biotherapy, INSERM, U1183 Montpellier (France)
3. Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier (France)
4. Centre de Recherche Saint-Antoine, INSERM, UMR 938, Sorbonne Universités, Université Paris 6, Paris (France)

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. - Highlights: • Induction of hepatic glycolytic and lipogenic genes upon CAR activation by TCPOBOP. • These effects are not mediated by the nuclear receptor LXR. • CAR activation resulted in hepatic lipid accumulation. • Pnpla3 expression is regulated by CAR in mouse liver and human hepatocytes.

• OSTI ID: 22689203
• Journal Information: Toxicology and Applied Pharmacology, Vol. 303; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANDROSTANES
BENZENE
CARBOHYDRATES
CARBOXYLIC ACIDS
CYTOCHROMES
GENES
GLYCEROL
KNOCK-OUT REACTIONS
LIPIDS
LIVER
LIVER CELLS
METABOLIC DISEASES
METABOLISM
MICE
PATHOGENESIS
PHENOBARBITAL
PHOSPHATES
PHOSPHOENOLPYRUVATE
PHOSPHOTRANSFERASES
POLYPEPTIDES
RECEPTORS
THYROID
THYROID HORMONES
TRANSCRIPTION
TRANSCRIPTION FACTORS