SIRT1 deacetylates and positively regulates the nuclear receptor LXR.
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 LXRalpha and K433 in LXRbeta) adjacent to the ligand-regulated activation domain AF2. SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRalpha 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.
Li
Xiaoling
X
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Zhang
Songwen
S
Blander
Gil
G
Tse
Jeanette G
JG
Krieger
Monty
M
Guarente
Leonard
L
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008239:Lysine / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008239:Lysine; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D056564:Sirtuin 1; D037761:Sirtuins; D013449:Sulfonamides; D014280:Triglycerides; D025801:Ubiquitin; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C470545:Sirt1 protein, mouse