Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

Amy K. Walker, Fajun Yang, Karen Jiang, Jun Yuan Ji, Jennifer L. Watts, Aparna Purushotham, Olivier Boss, Michael L. Hirsch, Scott Ribich, Jesse J. Smith, Kristine Israelian, Christoph H. Westphal, Joseph T. Rodgers, Toshi Shioda, Sarah L. Elson, Peter Mulligan, Hani Najafi, Josh C. Black, Jitendra K. Thakur, Lisa C. KadykJohnathan R. Whetstine, Raul Mostoslavsky, Pere Puigserver, Xiaoling Li, Nicholas J. Dyson, Anne C. Hart, Anders M. Näär

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD+-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.

Original languageEnglish
Pages (from-to)1403-1417
Number of pages15
JournalGenes and Development
Volume24
Issue number13
DOIs
Publication statusPublished - 1 Jul 2010
Externally publishedYes

Fingerprint

Sterol Regulatory Element Binding Proteins
Fasting
Cholesterol
Lipids
Homeostasis
Gene Expression
Fats
Obese Mice
Inhibition (Psychology)
Protein Stability
Ubiquitination
Liver
Sterols
Fatty Liver
Eukaryota
NAD
Genes
Cues
Mammals
Atherosclerosis

Keywords

  • Cholesterol
  • Fasting
  • Lipid
  • SIRT1
  • SREBP

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Walker, A. K., Yang, F., Jiang, K., Ji, J. Y., Watts, J. L., Purushotham, A., ... Näär, A. M. (2010). Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes and Development, 24(13), 1403-1417. https://doi.org/10.1101/gad.1901210

Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. / Walker, Amy K.; Yang, Fajun; Jiang, Karen; Ji, Jun Yuan; Watts, Jennifer L.; Purushotham, Aparna; Boss, Olivier; Hirsch, Michael L.; Ribich, Scott; Smith, Jesse J.; Israelian, Kristine; Westphal, Christoph H.; Rodgers, Joseph T.; Shioda, Toshi; Elson, Sarah L.; Mulligan, Peter; Najafi, Hani; Black, Josh C.; Thakur, Jitendra K.; Kadyk, Lisa C.; Whetstine, Johnathan R.; Mostoslavsky, Raul; Puigserver, Pere; Li, Xiaoling; Dyson, Nicholas J.; Hart, Anne C.; Näär, Anders M.

In: Genes and Development, Vol. 24, No. 13, 01.07.2010, p. 1403-1417.

Research output: Contribution to journalArticle

Walker, AK, Yang, F, Jiang, K, Ji, JY, Watts, JL, Purushotham, A, Boss, O, Hirsch, ML, Ribich, S, Smith, JJ, Israelian, K, Westphal, CH, Rodgers, JT, Shioda, T, Elson, SL, Mulligan, P, Najafi, H, Black, JC, Thakur, JK, Kadyk, LC, Whetstine, JR, Mostoslavsky, R, Puigserver, P, Li, X, Dyson, NJ, Hart, AC & Näär, AM 2010, 'Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP', Genes and Development, vol. 24, no. 13, pp. 1403-1417. https://doi.org/10.1101/gad.1901210
Walker, Amy K. ; Yang, Fajun ; Jiang, Karen ; Ji, Jun Yuan ; Watts, Jennifer L. ; Purushotham, Aparna ; Boss, Olivier ; Hirsch, Michael L. ; Ribich, Scott ; Smith, Jesse J. ; Israelian, Kristine ; Westphal, Christoph H. ; Rodgers, Joseph T. ; Shioda, Toshi ; Elson, Sarah L. ; Mulligan, Peter ; Najafi, Hani ; Black, Josh C. ; Thakur, Jitendra K. ; Kadyk, Lisa C. ; Whetstine, Johnathan R. ; Mostoslavsky, Raul ; Puigserver, Pere ; Li, Xiaoling ; Dyson, Nicholas J. ; Hart, Anne C. ; Näär, Anders M. / Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. In: Genes and Development. 2010 ; Vol. 24, No. 13. pp. 1403-1417.
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AU - Ji, Jun Yuan

AU - Watts, Jennifer L.

AU - Purushotham, Aparna

AU - Boss, Olivier

AU - Hirsch, Michael L.

AU - Ribich, Scott

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AU - Kadyk, Lisa C.

AU - Whetstine, Johnathan R.

AU - Mostoslavsky, Raul

AU - Puigserver, Pere

AU - Li, Xiaoling

AU - Dyson, Nicholas J.

AU - Hart, Anne C.

AU - Näär, Anders M.

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