Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

Noh, Kyoung Jin; Kim, Young Mi; Kim, Young Woo; Kim, Sang Geon

doi:10.1124/dmd.111.038414

Cited by 33 publications

(17 citation statements)

References 41 publications

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“…It has been reported that AMPKα1 is the most common catalytic subunit of AMPK in the liver (Stapleton et al 1996). Although previous studies reported that FXR activation resulted in AMPK activation (Noh et al 2011) or induced LKB1 expression (Lee et al 2012). In this current study, EE primarily activated AMPKα1, not AMPKα2.…”

Section: Discussionmentioning

confidence: 99%

Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats

Liu

Luo

et al. 2016

Arch Toxicol

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Estrogen-induced cholestasis occurs in many women who are susceptible due to pregnancy or hormone replacement therapy for postmenopausal syndrome. 17α-Ethinylestradiol (EE), as a synthetic estrogen, has been widely used to study the underlying mechanisms of estrogen-induced cholestasis. Recent studies have also reported that liver kinase B1 (LKB1)-mediated activation of AMP-activated protein kinase (AMPK) plays a critical role in the regulation of canalicular network formation. However, the role of AMPK in EE-induced cholestasis remains to be determined. In this study, the effects of EE (1–100 μM) on AMPK activation and the expression of farnesoid X receptor (FXR) and hepatic bile acid transporters were examined in vitro using 3D-cultured rat primary hepatocytes and in vivo using rat cholestasis models. We also used specific chemical agonist and antagonist of AMPK, AMPK subunit-specific antibodies and lentiviral shRNAs for AMPKα1 and AMPKα2 to delineate the role of AMPK in EE-induced cholestasis and potential cellular mechanisms. We found that EE-induced phosphorylation of AMPKα1 via extracellular-signal-regulated kinases (ERK1/2)-LKB1-mediated signaling pathways and subsequent nuclear translocation accounted for the down-regulation of FXR and bile acid transporters and disruption of bile acid homeostasis. Inhibition of AMPK activation using an AMPK antagonist Compound C (2 μM) or down-regulation of AMPKα1 using gene-specific shRNA attenuated EE-induced cholestasis both in vitro and in vivo. In conclusion, these results revealed that activation of cAMP-ERK-LKB1-AMPKα1 signaling pathway plays a critical role in EE-mediated dysregulation of the expression of FXR and bile acid transporters. AMPKα1 may represent an important therapeutic target for estrogen-induced cholestasis.

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Section: Discussionmentioning

confidence: 99%

Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats

Liu

Luo

et al. 2016

Arch Toxicol

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“…FXR (gene symbol NR1H4 ) is an important member of the nuclear hormone receptor family and is highly expressed in the liver, intestine, kidney, the adrenal gland, adipose tissue and heart (Houten et al 2007; Noh et al 2011). FXR acts as a ligand-activated transcription factor by binding to specific DNA motifs in the promoter regions of its target genes.…”

Section: Regulatory Genes and Signaling Pathways In The Livermentioning

confidence: 99%

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

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“…Because LKB1 is an upstream kinase of AMPK, FXR ligand treatment activated AMPK in hepatocytes, as shown in part previously. 16 Abrogation of CDCA-induced LKB1 phosphorylation by FXR knockdown supported the regulatory role of FXR in this event (Figure 5 B ). Consistently, FXR overexpression facilitated LKB1 phosphorylation (Figure 5 C ).…”

Section: Resultsmentioning

confidence: 58%

Farnesoid X Receptor Protects Hepatocytes From Injury by Repressing miR-199a-3p, Which Increases Levels of LKB1

Lee

Kim

et al. 2012

Gastroenterology

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BACKGROUND & AIMS Hepatocyte injury occurs during liver fibrogenesis. MicroRNAs (miRNA) regulate some of these processes, and some are regulated by the farnesoid X receptor (FXR). We investigated the effect of repression of specific miRNAs by FXR in hepatocyte injury using fibrotic liver tissue from patients and hepatocytes. METHODS We used immunohistochemistry or real-time polymerase chain reaction to analyze proteins and miRNAs in human and mouse liver samples. HepG2 cells were transfected with pre-miRNA, antisense oligonucleotides, small interfering RNAs, the 3′-untranslated region of liver kinase B1 (LKB1) (STK11), or constructs for overexpression, and analyzed. RESULTS Liver tissue from patients with severe fibrosis had lower levels of FXR and greater amounts of hepatocyte death than samples from patients with mild disease. Levels of several miRNAs changed when FXR expression was disrupted in the liver; one of these, miR-199a-3p, was significantly up-regulated in patients with severe fibrosis. Activation of FXR by its ligand reduced the level of miR-199a-3p in HepG2 cells. LKB1 messenger RNA was identified as a target of miR-199a-3p, and its expression was reduced in human fibrotic liver tissue. Overexpression of FXR or incubation of cultured hepatocytes with the FXR ligand up-regulated LKB1; LKB1 was not induced in cells transfected with miR-199a-3p. Incubation of HepG2 cells with FXR ligand, or injection of the ligand into mice, protected hepatocytes from injury and increased levels of LKB1; levels of miR-199a-3p were reduced compared with cells that were not incubated with the FXR ligand. Activation of FXR reduced mitochondrial dysfunction and oxidative stress and increased hepatocyte survival. CONCLUSIONS In hepatocytes, FXR represses production of miR-199a-3p. In fibrotic livers of humans and mice, FXR expression is reduced, increasing levels of miR-199a-3p, which reduces levels of LKB1. FXR therefore protects hepatocytes from injury by repressing miR-199a-3p and thereby increasing levels of LKB1.

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Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

Cited by 33 publications

References 41 publications

Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats

Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Farnesoid X Receptor Protects Hepatocytes From Injury by Repressing miR-199a-3p, Which Increases Levels of LKB1

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