期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 32, 期 7, 页码 1226-1236出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.05988-11
关键词
-
资金
- NIH, National Institute of Environmental Health Sciences [Z01 ES102205]
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 1 alpha (HNF1 alpha). SIRT1 deficiency in hepatocytes leads to decreased binding of HNF1 alpha 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 HNF1 alpha/FXR signaling pathway.
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