Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Wei-Dong Chen is active.

Publication


Featured researches published by Wei-Dong Chen.


Hepatology | 2008

Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response

Yan-Dong Wang; Wei-Dong Chen; Meihua Wang; Donna Yu; Barry M. Forman; Wendong Huang

The farnesoid X receptor (FXR) is a nuclear receptor that plays key roles in hepatoprotection by maintaining the homeostasis of liver metabolism. FXR null mice display strong hepatic inflammation and develop spontaneous liver tumors. In this report, we demonstrate that FXR is a negative modulator of nuclear factor κB (NF‐κB)–mediated hepatic inflammation. Activation of FXR by its agonist ligands inhibited the expression of inflammatory mediators in response to NF‐κB activation in both HepG2 cells and primary hepatocytes cultured in vitro. In vivo, compared with wild‐type controls, FXR−/− mice displayed elevated messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interferon‐inducible protein 10, and interferon‐γ in response to lipopolysaccharide (LPS). Examination of FXR−/− livers showed massive necroses and inflammation after treatment with LPS at a dose that does not induce significant liver damage or inflammation in wild‐type mice. Moreover, transfection of a constitutively active FXR expression construct repressed the iNOS, COX‐2, interferon‐inducible protein 10 and interferon‐γ mRNA levels induced by LPS administration. FXR activation had no negative effects on NF‐κB‐activated antiapoptotic genes, suggesting that FXR selectively inhibits the NF‐κB‐mediated hepatic inflammatory response but maintains or even enhances the cell survival response. On the other hand, NF‐κB activation suppressed FXR‐mediated gene expression both in vitro and in vivo, indicating a negative crosstalk between the FXR and NF‐κB signaling pathways. Our findings reveal that FXR is a negative mediator of hepatic inflammation, which may contribute to the critical roles of FXR in hepatoprotection and suppression of hepatocarcinogenesis. (HEPATOLOGY 2008;48:1632–1643.)


Hepatology | 2011

The G-Protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) in mice†‡§

Yan-Dong Wang; Wei-Dong Chen; Donna Yu; Barry M. Forman; Wendong Huang

Gpbar1 (TGR5), a membrane‐bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. TGR5 also displays strong attenuation of macrophage reactivity in vitro, but the physiological roles of TGR5 in inflammatory response, and its mechanism, is unknown. Here, we demonstrate that TGR5 is a negative modulator of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB)‐mediated inflammation. TGR5 activation suppresses the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor, alpha (IκBα), the translocation of p65, NF‐κB DNA‐binding activity, and its transcription activity. Furthermore, TGR5 activation enhances the interaction of IκBα and β‐arrestin2. Suppression of NF‐κB transcription activity and its target gene expression by TGR5 agonist are specifically abolished by the expression of anti‐β‐arrestin2 small interfering RNA. These results show that TGR5 suppresses the NF‐κB pathway by mediation of the interaction between IκBα and β‐arrestin2. In a lipopolysaccharide (LPS)‐induced inflammation model, TGR5−/− mice show more severe liver necroses and inflammation, compared with wild‐type (WT) mice. Activation of TGR5 by its agonist ligand inhibits the expression of inflammatory mediators in response to NF‐κB activation induced by LPS in WT, but not TGR5−/−, mouse liver. Conclusion: These findings identify TGR5 as a negative mediator of inflammation that may serve as an attractive therapeutic tool for immune and inflammatory liver diseases. (HEPATOLOGY 2011;)


Cell Research | 2008

FXR: a metabolic regulator and cell protector.

Yan-Dong Wang; Wei-Dong Chen; David D. Moore; Wendong Huang

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid, cholesterol, lipid, and glucose metabolism. Therefore, FXR is a potential drug target for a number of metabolic disorders, especially those related to the metabolic syndrome. More recently, our group and others have extended the functions of FXR to more than metabolic regulation, which include anti-bacterial growth in intestine, liver regeneration, and hepatocarcinogenesis. These new findings suggest that FXR has much broader roles than previously thought, and also highlight FXR as a drug target for multiple diseases. This review summarizes the basic information of FXR but focuses on its new functions.


Hepatology | 2009

Farnesoid X receptor alleviates age‐related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription

Wei-Dong Chen; Yan-Dong Wang; Lisheng Zhang; Steven Shiah; Meihua Wang; Fan Yang; Donna Yu; Barry M. Forman; Wendong Huang

Elucidating the mechanism of liver regeneration could lead to life‐saving therapy for a large number of patients, especially elderly patients, after segmental liver transplantation or resection of liver tumors. The forkhead box m1b (Foxm1b) transcription factor is required for normal liver regeneration. Here we report that Foxm1b is the first direct farnesoid X receptor (FXR) target gene known to be involved in cell cycle regulation and that aging regenerating livers have delayed activation of FXR, which results in defective induction of Foxm1b and thereby contributes to defective liver regeneration. An inverted repeat 0 (IR‐0) FXR response element, acting as an enhancer in intron 3 of the Foxm1b gene, was identified by a combination of transcriptional reporter, electrophoretic mobility shift, and chromatin immunoprecipitation assays. Diminished FXR binding to the IR‐0 element was found in aging regenerating livers. FXR activation by a novel ligand in aging livers induced Foxm1b expression and elevated hepatocyte DNA replication to about 70% of the levels found in young regenerating livers, which were specifically suppressed by hepatic expression of anti‐Foxm1b short hairpin RNA. Conclusion: Our results have revealed Foxm1b as the first known direct FXR target gene involved in cell cycle regulation and have demonstrated that defective activation of FXR could be an intrinsic defect in aging regenerating livers. Activation of FXR alone is largely able to alleviate age‐related liver regeneration defects. These findings highlight FXR as a potential target of drug design for promoting liver regeneration in older subjects. (HEPATOLOGY 2010.)


Hepatology | 2012

Promotion of liver regeneration/repair by farnesoid X receptor in both liver and intestine in mice

Lisheng Zhang; Yan-Dong Wang; Wei-Dong Chen; Xichun Wang; Guiyu Lou; Nian Liu; Min Lin; Barry M. Forman; Wendong Huang

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and is the primary bile acid receptor. We previously showed that FXR was required for the promotion of liver regeneration/repair after physical resection or liver injury. However, the mechanism by which FXR promotes liver regeneration/repair is still unclear. Here we show that both hepatic‐FXR and intestine‐FXR contributed to promote liver regeneration/repair after either 70% partial hepatectomy or carbon tetrachloride‐induced liver injury. Hepatic FXR, but not intestine FXR, is required for the induction of Foxm1b gene expression in liver during liver regeneration/repair. In contrast, intestine FXR is activated to induce FGF15 expression in intestine after liver damage. Ectopic expression of FGF15 was able to rescue the defective liver regeneration/repair in intestine‐specific FXR null mice. Conclusion: These results demonstrate that, in addition to the cell‐autonomous effect of hepatic FXR, the endocrine FGF15 pathway activated by FXR in intestine also participates in the promotion of liver regeneration/repair. (HEPATOLOGY 2012;56:2336–2343)


Molecular Endocrinology | 2008

Farnesoid X Receptor Protects Liver Cells from Apoptosis Induced by Serum Deprivation in Vitro and Fasting in Vivo

Yan-Dong Wang; Fan Yang; Wei-Dong Chen; Xiongfei Huang; Lily L. Lai; Barry M. Forman; Wendong Huang

The farnesoid X receptor (FXR) is a key metabolic regulator in the liver by maintaining the homeostasis of liver metabolites. Recent findings suggest that FXR may have a much broader function in liver physiology and pathology. In the present work, we identify a novel role of FXR in protecting liver cell from apoptosis induced by nutritional withdrawal including serum deprivation in vitro or starvation in vivo. Two FXR ligands, chenodeoxycholic acid (CDCA) and GW4064, rescued HepG2 cells from serum deprivation-induced apoptosis in a dose-dependent manner. This effect of FXR on apoptotic suppression was compromised when FXR was knocked down by short interfering RNA. Similarly, the effects of both CDCA and GW4064 were abolished after inhibition of the MAPK pathway by a specific inhibitor of MAPK kinase 1/2. Immunoblotting results indicated that FXR activation by CDCA and GW4064 induced ERK1/2 phosphorylation, which was attenuated by serum deprivation. In vivo, FXR(-/-) mice exhibited an exacerbated liver apoptosis and lower levels of phosphorylated-ERK1/2 compared to wild-type mice after starvation. In conclusion, our results suggest a novel role of FXR in modulating liver cell apoptosis.


Biochimica et Biophysica Acta | 2011

Nuclear bile acid receptor FXR in the hepatic regeneration

Wei-Dong Chen; Yan-Dong Wang; Zhipeng Meng; Lisheng Zhang; Wendong Huang

The liver can fully regenerate itself by a compensatory regrowth in response to partial hepatectomy or injury. This process consists of a variety of well-orchestrated phases and is mediated by many signals. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Bile acids are FXR physiological ligands. As a metabolic regulator, FXR plays key roles in regulating metabolism of bile acids, lipids and glucose. Recently, bile acid/FXR signaling pathway is shown to be required for normal liver regeneration. Furthermore, FXR promotes liver repair after injury and activation of FXR is able to alleviate age-related defective liver regeneration. These novel findings suggest that FXR-mediated bile acid signaling is an integrated component of normal liver regeneration machinery, and also highlight the potential use of FXR ligands to promote liver regeneration after segmental liver transplantation or resection of liver tumors. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.


Hepatology | 2012

Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver

Wei-Dong Chen; Xianghui Fu; Bingning Dong; Yan-Dong Wang; Steven Shiah; David D. Moore; Wendong Huang

Aberrant epigenetic alterations during development may result in long‐term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to the CAR‐specific ligand 1,4‐bis[2‐(3,5‐dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 mono‐, di‐, and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator activating signal cointegrator‐2 and histone demethylase JMJD2d participated in this CAR‐dependent epigenetic switch. Conclusion: Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. (HEPATOLOGY 2012)


Journal of Hepatology | 2011

Insufficient bile acid signaling impairs liver repair in CYP27−/− mice

Zhipeng Meng; Nian Liu; Xianghui Fu; Xiaoqiong Wang; Yan-Dong Wang; Wei-Dong Chen; Lisheng Zhang; Barry M. Forman; Wendong Huang

BACKGROUND & AIMS Previous studies indicate that bile acids (BAs) promote normal liver regeneration and repair after injury. However, the impact of insufficient BA signaling, which is observed in patients with BA sequestrant medication or cerebrotendinous xanthomatosis (CTX) disease, on liver injury is still unknown. Our aim is to determine the outcomes of reduced BA levels upon liver injury. METHODS Seventy percent partial hepatectomy (PH) and carbon tetrachloride (CCl(4)) treatment were performed using CYP27(-/-) mice, a genetic animal model with low BA levels. The liver repair of CYP27(-/-) mice after the treatments was characterized by histological staining, chemical analysis, and quantitative real-time PCR. RESULTS CYP27(-/-) mice exhibited enhanced CCl(4)-induce liver injury, and defective liver regeneration and prolonged steatosis after 70% PH. Due to the insufficient BA signaling, farnesoid X receptor (FXR) activities were significantly reduced in CYP27(-/-) livers after 70% PH. Activation of FXR by either 0.2% cholic acid feeding or oral infusion of an FXR agonist greatly promoted liver regeneration in CYP27(-/-) mice. CONCLUSIONS Normal physiological levels of BAs are required for liver repair. Patients with BA sequestrant medications or CTX disease due to CYP27 gene mutations may have an increased risk of liver failure, and treatment with FXR ligands can promote liver regeneration of patients with low BA levels.


Oncotarget | 2015

The G-protein-coupled bile acid receptor Gpbar1 (TGR5) suppresses gastric cancer cell proliferation and migration through antagonizing STAT3 signaling pathway

Cong Guo; Jia Su; Zhijun Li; Rui Xiao; Jianxun Wen; Yanyan Li; Meng Zhang; Xueting Zhang; Donna Yu; Wendong Huang; Wei-Dong Chen; Yan-Dong Wang

Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. Here we show that TGR5 is a suppressor of gastric cancer cell proliferation and migration through antagonizing STAT3 signaling pathway. We firstly show that TGR5 activation greatly inhibited proliferation and migration of human gastric cancer cells and strongly induced gastric cancer cell apoptosis. We then found that TGR5 activation antagonized STAT3 signaling pathway through suppressing the phosphorylation of STAT3 and its transcription activity induced by lipopolysaccharide (LPS) or interleukin-6. TGR5 overexpression with ligand treatment inhibited gene expression mediated by STAT3. It suggests that TGR5 antagonizes gastric cancer proliferation and migration at least in part by inhibiting STAT3 signaling. These findings identify TGR5 as a suppressor of gastric cancer cell proliferation and migration that may serve as an attractive therapeutic tool for human gastric cancer.

Collaboration


Dive into the Wei-Dong Chen's collaboration.

Top Co-Authors

Avatar

Yan-Dong Wang

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Wendong Huang

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Barry M. Forman

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Donna Yu

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Lisheng Zhang

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Jia Su

Beijing University of Chemical Technology

View shared research outputs
Top Co-Authors

Avatar

David D. Moore

Baylor College of Medicine

View shared research outputs
Top Co-Authors

Avatar

Fan Yang

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Meihua Wang

City of Hope National Medical Center

View shared research outputs
Top Co-Authors

Avatar

Nian Liu

City of Hope National Medical Center

View shared research outputs
Researchain Logo
Decentralizing Knowledge