1. Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way.
- Author
-
Marmugi A, Lukowicz C, Lasserre F, Montagner A, Polizzi A, Ducheix S, Goron A, Gamet-Payrastre L, Gerbal-Chaloin S, Pascussi JM, Moldes M, Pineau T, Guillou H, and Mselli-Lakhal L
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Line, Cells, Cultured, Constitutive Androstane Receptor, Female, Gene Expression Regulation drug effects, Hep G2 Cells, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Lipase genetics, Lipase metabolism, Liver drug effects, Liver X Receptors genetics, Liver X Receptors metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins genetics, Nuclear Proteins metabolism, Phenobarbital pharmacology, Pyridines pharmacology, RNA, Messenger metabolism, Transcription Factors genetics, Transcription Factors metabolism, Fatty Liver metabolism, Lipogenesis drug effects, Liver metabolism, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear genetics
- 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF