SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation

Gaëlle Laurent, Vincent C.J. de Boer, Lydia W.S. Finley, Meredith Sweeney, Hong Lu, Thaddeus T. Schug, Yana Cen, Seung Min Jeong, Xiaoling Li, Anthony A. Sauve, Marcia C. Haigis

Research output: Contribution to journalArticle

Abstract

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferatoractivated receptor (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.

Original languageEnglish (US)
Pages (from-to)4552-4561
Number of pages10
JournalMolecular and cellular biology
Volume33
Issue number22
DOIs
StatePublished - Nov 15 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Laurent, G., de Boer, V. C. J., Finley, L. W. S., Sweeney, M., Lu, H., Schug, T. T., Cen, Y., Jeong, S. M., Li, X., Sauve, A. A., & Haigis, M. C. (2013). SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Molecular and cellular biology, 33(22), 4552-4561. https://doi.org/10.1128/MCB.00087-13