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

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 04/2012; 32(7):1226-36. DOI: 10.1128/MCB.05988-11
Source: PubMed

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.

Download full-text


Available from: Dong-hyun Kim, Mar 31, 2015
24 Reads
  • Source
    • "We have shown that acetylation of FXR is tightly regulated by p300 and SIRT1 under physiological conditions, which is important for dynamic transcriptional regulation, but that in obesity, SIRT1 levels and activity are low, resulting in persistently elevated acetylation of FXR (Kemper et al, 2009). Further, FXR acetylation was elevated in liver-specific SIRT1-KO mice (Purushotham et al, 2012), and conversely, acetylation of FXR as well as that of SREBP-1c, PGC-1a, and NF-jB was decreased by overexpression of SIRT1 (Kemper et al, 2009; Ponugoti et al, 2010; Choi et al, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. © 2014 The Authors.
    The EMBO Journal 11/2014; 34(2). DOI:10.15252/embj.201489527 · 10.43 Impact Factor
  • Source
    • "Down regulation of hepatic SIRT1 increases FXR acetylation, which inhibits its heterodimerisation with the Retinoid X receptor (RXR)α and therefore, its transcriptional activity [34]. Hence, SIRT1 deletion in liver is sufficient to downregulate FXR-related transcriptional programs and lead to the formation of cholesterol gallstones [35]. As for LXR, ligand binding promotes the interaction with SIRT1 and subsequent deacetylation on Lys 432 (LXRα) and on Lys 433 (LXRβ), promoting their activation [33]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: SIRT1 has attracted a lot of interest since it was discovered as a mammalian homolog of Sir2, a protein that influences longevity in yeast. Intensive early research suggested a key role of SIRT1 in mammalian development, metabolic flexibility and oxidative metabolism. However, it is the growing body of transgenic models that are allowing us to clearly define the true range of SIRT1 actions. In this review we aim to summarize the most recent lessons that transgenic animal models have taught us about the role of SIRT1 in mammalian metabolic homeostasis and lifespan.
    Molecular Metabolism 02/2014; 3(1):5-18. DOI:10.1016/j.molmet.2013.10.006
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sirtuin 1 (Sirt1) has been the focus of intense scrutiny because of its longevity activity. Recent studies also revealed the important role of Sirt1 in metabolic liver diseases. The present study was designed to elucidate the pathophysiological significance of Sirt1 in CCl(4)-induced acute liver injury (ALI). The expression of Sirt1 in liver tissue of mice with CCl(4)-induced ALI was determined by real-time polymerase chain reaction and western blotting. Sirt1 inhibitor nicotinamide (NAM) was administrated to investigate the role of Sirt1 in hepatocyte damage, leukocyte infiltration, and proinflammatory cytokine production. Results indicated that the messenger RNA and protein level of Sirt1 in the liver was gradually increased after CCl(4) administration. Inhibition of Sirt1 by its inhibitor (NAM) exacerbated liver injury, as evidenced by increased serum aminotransferases (alanine aminotransferase and aspartate aminotransferase) levels and more-severe histological damage. The worst liver injury was accompanied by higher myeloperoxidase acitivity in liver tissue and increased circulating levels of both tumor necrosis factor alpha and interleukin-6. These data indicated that the induction of Sirt1 might provide protective effects during CCl(4)-induced ALI. These findings suggest that Sirt1 might be an endogenous hepatoprotective target with potential pharmacological value in inflammation-based liver diseases.
    Drug and Chemical Toxicology 08/2012; 36(3). DOI:10.3109/01480545.2012.710630 · 1.23 Impact Factor
Show more