Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene

Rongya Tao, Dan Wei, Hanlin Gao, Yunlong Liu, Ronald A. Depinho, X. Dong

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72 Citations (Scopus)

Abstract

FoxO transcription factors have been implicated in lipid metabolism; however, the underlying mechanisms are not well understood. Here, in an effort to elucidate such mechanisms, we examined the phenotypic consequences of liver-specific deletion of three members of the FoxO family: FoxO1, FoxO3, and FoxO4. These liver-specific triply null mice, designated LTKO, exhibited elevated triglycerides in the liver on regular chow diet. More remarkably, LTKO mice developed severe hepatic steatosis following placement on a high fat diet. Further analyses revealed that hepatic NAD+ levels and Sirt1 activity were decreased in the liver of the LTKO mice relative to controls. At the mechanistic level, expression profile analyses showed that LTKO livers had significantly down-regulated expression of the nicotinamide phosphoribosyltransferase (Nampt) gene encoding the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis. Luciferase reporter assays and chromatin immunoprecipitation analyses demonstrated that Nampt is a transcriptional target gene of FoxOs. Significantly, overexpression of Nampt gene reduced, whereas knockdown increased, hepatic triglyceride levels in vitro and in vivo. Thus, FoxOs control the Nampt gene expression and the NAD + signaling in the regulation of hepatic triglyceride homeostasis.

Original languageEnglish
Pages (from-to)14681-14690
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number16
DOIs
StatePublished - Apr 22 2011

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Nicotinamide Phosphoribosyltransferase
Lipid Metabolism
Liver
Genes
Modulation
NAD
Triglycerides
Nutrition
Salvaging
Gene encoding
Biosynthesis
Luciferases
Gene expression
Chromatin
Assays
Transcription Factors
Fats
Chromatin Immunoprecipitation
High Fat Diet
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. / Tao, Rongya; Wei, Dan; Gao, Hanlin; Liu, Yunlong; Depinho, Ronald A.; Dong, X.

In: Journal of Biological Chemistry, Vol. 286, No. 16, 22.04.2011, p. 14681-14690.

Research output: Contribution to journalArticle

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AU - Dong, X.

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