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CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis

Min Jun Jang1, Ui-Hyun Park2, Jeong Woo Kim1

  • 1Department of Molecular Biology, Dankook University, Cheonan-si, Chungnam, 31116, Korea.

Cell Death & Disease
|December 14, 2017
PubMed

Insights

CDK2-associated cullin 1 (CACUL1) represses adipocyte differentiation by regulating Peroxisome proliferator-activated receptor γ (PPARγ) signaling. Its depletion activates PPARγ, offering potential anti-obesity strategies.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cell Biology

Background:

  • Peroxisome proliferator-activated receptor γ (PPARγ) is crucial for adipocyte differentiation and obesity development.
  • Epigenetic regulation of PPARγ by histone modification is not well understood.

Purpose of the Study:

  • To investigate the role of CDK2-associated cullin 1 (CACUL1) in regulating PPARγ activity and adipogenesis.
  • To elucidate the epigenetic mechanisms underlying CACUL1's function in PPARγ signaling.

Main Methods:

  • Identified CACUL1 as a novel SIRT1 interacting protein.
  • Investigated CACUL1 binding to PPARγ and its effect on transcriptional activity.
  • Analyzed histone modifications (acetylation and methylation) at PPARγ-responsive gene promoters upon CACUL1 depletion.
  • Utilized 3T3-L1 cells and human adipose-derived stem cells for experiments.
  • Performed RNA sequencing for gene expression profiling.

Main Results:

  • CACUL1 directly binds to PPARγ and represses its transcriptional activity and adipogenic potential.
  • CACUL1 depletion leads to decreased SIRT1 and increased LSD1 recruitment to PPARγ promoters.
  • This results in increased histone H3K9 acetylation, decreased H3K9 methylation, and enhanced PPARγ activation during adipogenesis.
  • Fasting or resveratrol treatment reversed these effects.
  • RNA sequencing confirmed CACUL1's repressive role in PPARγ activation and fat accumulation.
  • CACUL1 function was confirmed in human adipose-derived stem cells.

Conclusions:

  • CACUL1 acts as a key regulator of PPARγ signaling through the interplay of SIRT1 and LSD1.
  • Understanding CACUL1's mechanism provides insights into potential anti-obesity therapeutic strategies.

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