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HDAC3 interacts with sumoylated C/EBPα to negatively regulate the LXRα expression in rat hepatocytes

Juan Ren1, Dongmin Li, Yue Li

  • 1Department of Genetics and Molecular Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, PR China.

Molecular and Cellular Endocrinology
|May 4, 2013
PubMed

Insights

Histone deacetylase 3 (HDAC3) interacts with sumoylated C/EBPα to negatively regulate liver X receptor alpha (LXRα) expression in hepatocytes. This interaction is crucial for controlling LXRα transcription in response to high-fat diets.

Area of Science:

  • Molecular biology
  • Hepatology
  • Biochemistry

Background:

  • High-fat diets induce changes in key metabolic regulators like liver X receptor alpha (LXRα).
  • Histone deacetylase 3 (HDAC3) and CCAAT/enhancer binding protein alpha (C/EBPα) are implicated in metabolic regulation but their precise roles in LXRα expression are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which HDAC3 and C/EBPα regulate LXRα expression in hepatocytes.
  • To investigate the interplay between HDAC3, C/EBPα, and LXRα in a high-fat diet model.

Main Methods:

  • Utilized a high-fat-diet E3 rat model and hepatocyte cell lines (CBRH-7919).
  • Employed techniques including stable expression (pEGFP-Hdac3, shRNA-Hdac3), transient transfection, 5'-serial deletion reporter analysis, Chromatin Immunoprecipitation (ChIP), Co-immunoprecipitation (Co-IP), and quantitative Real-Time PCR (qRT-PCR).
  • Investigated protein-protein interactions, promoter activity, and the role of C/EBPα sumoylation.

Main Results:

  • HDAC3 negatively regulates LXRα expression and its target genes.
  • C/EBPα upregulates LXRα expression and enhances LXRα promoter activity.
  • HDAC3 interacts with C/EBPα, and this interaction is modulated by C/EBPα sumoylation at lysine 159.
  • Sumoylated C/EBPα binds more effectively with HDAC3, leading to repression of LXRα promoter activity.

Conclusions:

  • HDAC3 interacts with sumoylated C/EBPα to negatively control LXRα expression in hepatocytes.
  • This molecular complex plays a significant role in regulating LXRα transcription, particularly under conditions mimicking high-fat diets.
  • Sumoylation of C/EBPα is a key event mediating the repressive effect of the HDAC3-C/EBPα complex on LXRα transcription.

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