title: Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1α/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice.
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.
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Purushotham
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Julie F
authors.initials: JF
authors.lastname: Foley
authors.forename: Xingjian
authors.initials: X
authors.lastname: Yan
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D042882:Gallstones / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002784:Cholesterol; D051538:Hepatocyte Nuclear Factor 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D056564:Sirtuin 1; D000099150:Receptor, Farnesoid X-Activated; C470545:Sirt1 protein, mouse