Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes

• Published in: Journal of hepatology Vol. 55; no. 1; pp. 145 - 153
• Main Authors: Dubuquoy, Céline, Robichon, Céline, Lasnier, Françoise, Langlois, Clotilde, Dugail, Isabelle, Foufelle, Fabienne, Girard, Jean, Burnol, Anne-Françoise, Postic, Catherine, Moldes, Marthe
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.07.2011; Elsevier
• Subjects: Adiponutrin; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Binding Sites - genetics; Biological and medical sciences; ChREBP; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - metabolism; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation - drug effects; Glucose - pharmacology; HEK293 Cells; Hep G2 Cells; Hepatic steatosis; Hepatocytes - drug effects; Hepatocytes - metabolism; HepG2; Humans; IHH; In Vitro Techniques; Insulin - pharmacology; Life Sciences; Lipase - genetics; Lipogenesis; Liver; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; NAFLD; Non-alcoholic Fatty Liver Disease; Nuclear Proteins - metabolism; Nutritional Status; Other diseases. Semiology; Phospholipases A2, Calcium-Independent - genetics; PNPLA3; Promoter Regions, Genetic; SREBP1c; Sterol Regulatory Element Binding Protein 1 - metabolism; Transcription Factors - metabolism; FFA; NAFLD; ATGL; Liver; SRE; IHH; GFP; HEK293; SNP; HepG2; SREBP1c; SCD1; ChoRE; Lipogenesis; Adiponutrin; Hepatic steatosis; NASH; ChREBP; TG; PNPLA3; FAS; SREBP1c-DN; ChIP-chip; pfu; ADPN; L-PK; liver-pyruvate kinase; non-alcoholic fatty liver disease; single nucleotide polymorphism; sterol regulatory element binding protein1c; free fatty acids; carbohydrate response element; sterol response element; adiponutrin; adipose triglyceride lipase; patatin-like phospholipase domain containing protein; human embryonic kidney cells; carbohydrate-response element-binding protein; sterol regulatory element binding protein-1c-dominant negative; plaque-forming units; triglycerides; green fluorescent protein; immortalized human hepatocytes; stearoyl-CoA desaturase 1; fatty acid synthase; chromatin immunoprecipitation combined with genome tiling arrays; human hepatocellular carcinoma cell line; non-alcoholic steatohepatitis; Human; Rodentia; Hepatic disease; Gene expression; Vertebrata; Mammalia; Fatty liver; Hepatocyte; Mouse; Animal; Gastroenterology; Digestive diseases; Transcription factor
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2010.10.024

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. 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. 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. 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.