SIRT1 Deacetylates and Positively Regulates the Nuclear Receptor LXR

Xiaoling Li, Songwen Zhang, Gil Blander, Jeanette G. Tse, Monty Krieger, Leonard Guarente

Research output: Contribution to journalArticle

Abstract

The NAD+-dependent deacetylase Sir2 regulates life span in lower eukaryotes. The mammalian ortholog SIRT1 regulates physiological processes including apoptosis, fat metabolism, glucose homeostasis, and neurodegeneration. Here we show that SIRT1 is a positive regulator of liver X receptor (LXR) proteins, nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRα and K433 in LXRβ) adjacent to the ligand-regulated activation domain AF2. SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRα by this sirtuin. Loss of SIRT1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis. Our findings suggest that deacetylation of LXRs by SIRT1 may be a mechanism that affects atherosclerosis and other aging-associated diseases.

Original languageEnglish (US)
Pages (from-to)91-106
Number of pages16
JournalMolecular cell
Volume28
Issue number1
DOIs
StatePublished - Oct 12 2007

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Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Li, X., Zhang, S., Blander, G., Tse, J. G., Krieger, M., & Guarente, L. (2007). SIRT1 Deacetylates and Positively Regulates the Nuclear Receptor LXR. Molecular cell, 28(1), 91-106. https://doi.org/10.1016/j.molcel.2007.07.032