Hepatic Deletion of SIRT1 Decreases Hepatocyte Nuclear Factor 1alpha/Farnesoid X Receptor Signaling and Induces Formation of Cholesterol Gallstones in Mice.

Purushotham A, Xu Q, Lu J, Foley JF, Yan X, Kim DH, Kemper JK, Li X.
Journal   Mol Cell Biol.
Species  
Analytes Measured   Insulin , Leptin
Matrix Tested   Serum
Year   2012
Volume   32
Page Numbers   1226-1236
Application   Metabolic
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.

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