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

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• 作者：Cé ; line Dubuquoy¹ ; ² ; ³ ; Cé ; line Robichon¹ ; ² ; ³ ; Franç ; oise Lasnier⁴ ; ⁵ ; Clotilde Langlois⁴ ; ⁵ ; Isabelle Dugail⁴ ; ⁵ ; Fabienne Foufelle⁴ ; ⁵ ; Jean Girard¹ ; ² ; ³ ; Anne-Franç ; oise Burnol¹ ; ² ; ³ ; Catherine Postic¹ ; ² ; ³ ; Marthe Moldes¹ ; ² ; ³ ; ^{marthe.moldes@inserm.fr"" rel=""nofollow}
• 关键词：Adiponutrin ; PNPLA3 ; SREBP1c ; ChREBP ; Lipogenesis ; Liver ; IHH ; HepG2 ; NAFLD ; Hepatic steatosis
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：55
• 期：1
• 页码：145-153
• 全文大小：939 K

文摘

Background & Aims

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.