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

Dubuquoy, Caroline; Robichon, Céline; Lasnier, Françoise; Langlois, Clotilde; Dugail, Isabelle; Foufelle, Fabienne; Girard, Jean; Burnol, Anne-Françoise; Postic, Catherine; Moldes, Marthe

doi:10.1016/j.jhep.2010.10.024

Cited by 114 publications

(97 citation statements)

References 47 publications

(76 reference statements)

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“…Vice versa, a MLXIPL downregulation occurs after p62 overexpression, while SREBF1 is activated. In fact, the literature reports that SREBF1 overexpression reduces MLXIPL expression ( 41 ). Because MLXIPL knockout animals show improved ( 69 ), i.e., ACACA ( 67 ), low levels promote the generation of malonyl-CoA via ACACA.…”

Section: Discussionmentioning

confidence: 99%

“…In order to study the mechanisms responsible for hepatic lipid alterations, we employed HepG2 cells, which are able to develop cellular steatosis and are frequently used for respective mechanistic studies ( 15,(41)(42)(43)(44). The fatty acid chain length, in fact, depended on the presence of p62; when p62 was knocked down in HepG2 cells, increased levels of C16 fatty acids were detectable ( Table 2 ), so that the ratio of C18 to C16 fatty acids decreased ( Fig.…”

Section: Characterization Of Steatosismentioning

confidence: 99%

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The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Laggai

Kessler

Boettcher

et al. 2014

Journal of Lipid Research

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Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common liver disorder in Western countries with a prevalence of 20-30% of the adult population ( 1, 2 ). There is a strong correlation between the characteristics of the metabolic syndrome, such as obesity and diabetes mellitus, and NAFLD/nonalcoholic steatohepatitis (NASH) ( 3 ).The "two-hit" hypothesis represents a common model to describe the development and progression of fatty liver diseases. A simple steatosis can stand for the fi rst step in early liver pathogenesis ( 4, 5 ). The progression from simple steatosis to NASH requires a "second hit" mediated by reactive oxygen species and release of infl ammatory cytokines ( 6 ). This infl ammatory environment can result in hepatic cirrhosis and fi nally in hepatocellular carcinoma (HCC) ( 7 ).The development of hepatosteatosis can be induced by different mechanisms. The synthesis of lipids is regulated in a complex interplay induced by a set of lipogenic transcription factors, among which liver X receptor ␣ (LXR-␣ / NR1H3), sterol regulatory element binding transcription factor 1 (SREBF1/SREBP1), and carbohydrate responsive element binding protein (ChREBP/MLXIPL) represent the most important ones ( 8 ). In this context, the fact that MLXIPL controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression ( 9 ) illustrates the Abstract Liver-specifi c overexpression of the insulin-like growth factor 2 ( IGF2 ) mRNA binding protein p62/ IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 . Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These fi ndings underline the detrimental role of p62 in liver disease. -Laggai, S., S. M. Kessler, S.

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Section: Discussionmentioning

confidence: 99%

Section: Characterization Of Steatosismentioning

confidence: 99%

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Laggai

Kessler

Boettcher

et al. 2014

Journal of Lipid Research

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“…(SREBP-1c) and carbohydrate response element binding protein (ChREBP) [74][75][76]. In human stellate cells, PNPLA3 is also downregulated by intracellular retinol levels [72].…”

Section: Reviewmentioning

confidence: 99%

PNPLA3 gene in liver diseases

Trépo

Romeo

Zucman‐Rossi

et al. 2016

Journal of Hepatology

214

187

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“…ChREBP and Max-like protein X (Mlx) form heterodimers [4,5] and bind to the carbohydrate response element (ChoRE), which is composed of two E-boxes separated by five base pairs (CABGTG-nnCnG-nGnSTG) [6][7][8]. The ChREBP/Mlx heterodimer regulates glucose and lipid metabolism through regulation of the glycolytic, gluconeogenic, and lipogenic gene expression [2,5,[8][9][10][11][12] (Table 1). Moreover, ChREBP regulates gene transcription, circadian rhythm, hormones and their receptors, and the redox signal [13][14][15][16][17][18][19][20][21] (Table 1).…”

Section: The Regulation Of Chrebp Transactivitymentioning

confidence: 99%

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

Iizuka

2013

Endocr J

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Abstract. Carbohydrate response element binding protein (ChREBP) is a transcription factor activated by glucose that is highly expressed in liver, pancreatic β-cells, brown and white adipose tissues, and muscle. We reported that hepatic suppression of the Chrebp gene improves hepatic steatosis, glucose intolerance, and obesity in genetically obese mice. Moreover, we have studied the role of ChREBP with special reference to feedforward and feedback looping in liver and pancreatic β-cells. Recently, several groups reported that (1) glucose activates ChREBP-α transactivity and in turn ChREBP-α induces ChREBP-β on both transcriptional and translational levels in adipose tissues, and (2) ChREBP regulates glucose transporter type 4 mRNA levels, which may affect glucose uptake in adipose tissues. Moreover, in adipose tissues of obese patients, Chrebpb mRNA levels were much lower than those in lean subjects, while the levels were much higher in liver of obese patients than those in lean subjects. These findings suggest that Chrebpb mRNA levels are different in various tissues and probably in the stages of diabetes mellitus. Herein, we review recent progress in the study of ChREBP with special references to (1) the mechanisms regulating ChREBP transactivity (posttranslational modifications, intramolecular glucose sensing module, feedforward mechanism, and the feedback loop between ChREBP and its target genes), and (2) the role of ChREBP in liver, pancreatic islets and adipose tissues. Understanding the role of ChREBP in each tissue will provide important insight into the pathogenesis of metabolic syndrome.

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

Cited by 114 publications

References 47 publications

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

PNPLA3 gene in liver diseases

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

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