GW4064, a farnesoid X receptor agonist, upregulates adipokine expression in preadipocytes and HepG2 cells

Xin, Xuegang; Zhong, Meifeng; Yang, Gong‐Li; Yao, Peng; Zhang, Yali; Zhu, Wei

doi:10.3748/wjg.v20.i42.15727

Cited by 9 publications

(7 citation statements)

References 58 publications

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“…This receptor is well known for its capacity to mediate insulin signaling via augmenting the release of adiponectin and the translocation of GLUT4 to the surface of skeletal myocytes and adipocytes [47,48]. Other studies have documented the cross-talk between FXR and PPARγ in alleviating liver fibrosis [49] and other metabolic diseases like nonalcoholic fatty liver disease [50]. Hence, these data may correlate to the present work and emphasize the possible involvement of these two receptors in mediating CDCA-related neuroprotection and insulin sensitivity, seen in our study.…”

Section: Discussionmentioning

confidence: 99%

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

2019

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Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

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Section: Discussionmentioning

confidence: 99%

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

2019

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“…3 , IR9 is identified as a novel FXRE that is involved in up-regulation of SOCS3 in HCC cells, which means SOCS3 is a new direct target gene of FXR. Besides, previous studies have demonstrated that another nuclear receptor PPAR γ could promote SOCS3 expression [ 8 , 31 ], and FXR could up-regulate PPAR γ [ 32 , 33 ]. So FXR may also indirectly enhance the expression of SOCS3 via inducing PPAR γ.…”

Section: Discussionmentioning

confidence: 99%

FXR induces SOCS3 and suppresses hepatocellular carcinoma

Guo

Zhang

et al. 2015

Oncotarget

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Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC.

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“…Leptin‐deficient ob/ob mice display markedly reduced levels of energy expenditure and become an important model for MetS study (Flier, 2004). Several FXR agonists have been reported to enhance the expression of leptin in 3T3‐L1 cells and adipose tissue (Shihabudeen, Roy, James, & Thirumurugan, 2015; Xin et al, 2014). In breast malignancy, FXR activation has been reported to inhibit leptin signalling (Giordano et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Extract of Schisandra chinensis fruit protects against metabolic dysfunction in high‐fat diet induced obese mice via FXR activation

Song

et al. 2020

Phytotherapy Research

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Schisandra chinensis fruit has been shown to restore carbohydrate-and lipid-metabolic disorders and has anti-hepatotoxicity and anti-hepatitis activities. However, the molecular targets mediating the pharmacological properties of S. chinensis fruit have not been clarified. Here, we assayed the effects of S. chinensis fruit ethanol extract (SCE) on farnesoid X receptor (FXR) transactivity. The pharmacological effects of SCE (1 g/100 g diet) were assessed in high-fat diet (HFD)-fed C57BL/6 mice and ob/ob mice. The FXR and Fgf15 signalling pathways were evaluated by FXR silencing, ELISA, Western blot and RT-PCR analyses. The results showed that SCE treatment increased FXR transcription activity and improved obesity, hypercholesteremia and fatty liver in HFD-fed mice, while it had limited effects on ob/ob mice. Our study suggests that SCE treatment may improve HFDinduced metabolic disorders through pharmacological activation of FXR/Fgf15 signalling, and such beneficial effects of SCE may require leptin participation.

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GW4064, a farnesoid X receptor agonist, upregulates adipokine expression in preadipocytes and HepG2 cells

Abstract: The FXR agonist through regulating, at least partially, the expression of adipokines and their receptors could offer an innovative way for counteracting the progress of metabolic diseases such as nonalcoholic fatty liver disease.

Cited by 9 publications

References 58 publications

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

FXR induces SOCS3 and suppresses hepatocellular carcinoma

Extract of Schisandra chinensis fruit protects against metabolic dysfunction in high‐fat diet induced obese mice via FXR activation

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