SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.
The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes.
Ponugoti
Bhaskar
B
Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801, USA.
Kim
Dong-Hyun
DH
Xiao
Zhen
Z
Smith
Zachary
Z
Miao
Ji
J
Zang
Mengwei
M
Wu
Shwu-Yuan
SY
Chiang
Cheng-Ming
CM
Veenstra
Timothy D
TD
Kemper
Jongsook Kim
JK
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D056564:Sirtuin 1 / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
D007328:Insulin; D008055:Lipids; D051780:Sterol Regulatory Element Binding Protein 1; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7
15220471
Cold Spring Harb Symp Quant Biol. 2007;72:483-8
18419308
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5987-92
9600904
Nature. 2006 Nov 16;444(7117):337-42
17086191
Biochem Soc Trans. 2002 Nov;30(Pt 6):1091-5
12440980
J Clin Invest. 1997 Mar 1;99(5):846-54
9062341
Cell Metab. 2006 Jun;3(6):429-38
16753578
J Biol Chem. 2001 Sep 14;276(37):34816-23
11443121
Cell Metab. 2009 Apr;9(4):327-38
19356714
Mol Endocrinol. 2007 Nov;21(11):2698-712
17636037
J Biol Chem. 2000 Oct 20;275(42):32379-82
10934219
Mol Cell Biol. 2004 Sep;24(17):7707-19
15314177
Mol Cell Biol. 2007 Feb;27(4):1407-24
17145766
Mol Cell Biol. 2004 Sep;24(18):8288-300
15340088
Genes Dev. 2010 Jul 1;24(13):1403-17
20595232
Cell. 2006 Dec 15;127(6):1109-22
17112576
Cell Metab. 2009 Nov;10(5):392-404
19883617
Mol Cell Biol. 2003 Apr;23(7):2587-99
12640139
Mol Cell Biol. 2009 Sep;29(17):4864-72
19564420
Prog Lipid Res. 2001 Nov;40(6):439-52
11591434
J Biol Chem. 2005 Apr 22;280(16):16456-60
15716268
Genes Dev. 2009 Apr 15;23(8):986-96
19390091
Mol Cell. 2005 Jan 21;17(2):251-64
15664194
J Clin Invest. 1998 Jan 1;101(1):1-9
9421459
Science. 2006 Apr 14;312(5771):195-7; author reply 195-7
16614198
FEBS Lett. 2008 Jan 9;582(1):46-53
18036349
J Biol Chem. 1999 Oct 15;274(42):30028-32
10514488
J Biol Chem. 2009 Feb 27;284(9):5885-95
19126544
Mol Cell. 2007 Oct 12;28(1):91-106
17936707
Cell. 1997 May 2;89(3):331-40
9150132
Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G892-8
18239056
Diabetes. 2005 May;54(5):1314-23
15855315
EMBO J. 2000 Mar 15;19(6):1176-9
10716917
J Biol Chem. 2008 Dec 12;283(50):35086-95
18842595
Nature. 2005 Mar 3;434(7029):113-8
15744310
Endocr Rev. 2003 Feb;24(1):78-90
12588810
J Biol Chem. 2004 Dec 10;279(50):51999-2006
15466874
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12861-6
17646659
Nat Med. 2004 Apr;10(4):355-61
15057233
Cell Metab. 2005 Jun;1(6):379-91
16054087
Cell Metab. 2008 Nov;8(5):347-58
19046567
Mol Endocrinol. 2007 Aug;21(8):1745-55
17456799
Hum Gene Ther. 2004 Dec;15(12):1287-92
15684704
J Biol Chem. 2006 Sep 29;281(39):28745-54
16885156
J Biol Chem. 2009 Apr 17;284(16):10446-52
19244231