Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1α/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice

Aparna Purushotham, Qing Xu, Jing Lu, Julie F. Foley, Xingjian Yan, Dong Hyun Kim, Jongsook Kim Kemper, Xiaoling Li

Research output: Contribution to journalArticlepeer-review

Abstract

SIRT1, a highly conserved NAD+-dependent protein deacetylase, is a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although SIRT1 has been implicated in a number of hepatic metabolic processes, the mechanisms by which hepatic SIRT1 modulates bile acid metabolism are still not well understood. Here we report that deletion of hepatic SIRT1 reduces the expression of farnesoid X receptor (FXR), a nuclear receptor that regulates bile acid homeostasis. We provide evidence that SIRT1 regulates the expression of FXR through hepatocyte nuclear factor 1α (HNF1α). SIRT1 deficiency in hepatocytes leads to decreased binding of HNF1α to the FXR promoter. Furthermore, we show that hepatocyte-specific deletion of SIRT1 leads to derangements in bile acid metabolism, predisposing the mice to development of cholesterol gallstones on a lithogenic diet. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of hepatic bile acid homeostasis through the HNF1α/FXR signaling pathway.

Original languageEnglish (US)
Pages (from-to)1226-1236
Number of pages11
JournalMolecular and cellular biology
Volume32
Issue number7
DOIs
StatePublished - Apr 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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