SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation

Manuel Roqueta-Rivera, Ryan M. Esquejo, Peter E. Phelan, Katalin Sandor, Bence Daniel, Fabienne Foufelle, Jun Ding, Xiaoman Li, Sepideh Khorasanizadeh, Timothy F. Osborne

Research output: Contribution to journalArticle

Abstract

Transcriptional and chromatin regulations mediate the liver response to nutrient availability. The role of chromatin factors involved in hormonal regulation in response to fasting is not fully understood. We have identified SETDB2, a glucocorticoid-induced putative epigenetic modifier, as a positive regulator of GR-mediated gene activation in liver. Insig2a increases during fasting to limit lipid synthesis, but the mechanism of induction is unknown. We show Insig2a induction is GR-SETDB2 dependent. SETDB2 facilitates GR chromatin enrichment and is key to glucocorticoid-dependent enhancer-promoter interactions. INSIG2 is a negative regulator of SREBP, and acute glucocorticoid treatment decreased active SREBP during refeeding or in livers of Ob/Ob mice, both systems of elevated SREBP-1c-driven lipogenesis. Knockdown of SETDB2 or INSIG2 reversed the inhibition of SREBP processing. Overall, these studies identify a GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming and identify SETDB2 as a potential target for metabolic disorders with aberrant glucocorticoid actions.

Original languageEnglish (US)
Pages (from-to)474-484
Number of pages11
JournalCell Metabolism
Volume24
Issue number3
DOIs
StatePublished - Sep 13 2016

Keywords

  • SETDB2
  • SREBP
  • fasting liver
  • glucocorticoid receptor
  • insig2

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Roqueta-Rivera, M., Esquejo, R. M., Phelan, P. E., Sandor, K., Daniel, B., Foufelle, F., Ding, J., Li, X., Khorasanizadeh, S., & Osborne, T. F. (2016). SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation. Cell Metabolism, 24(3), 474-484. https://doi.org/10.1016/j.cmet.2016.07.025