Hesperidin alleviates cholestasis via activation of the farnesoid X receptor in vitro and in vivo

2020 ◽  
Vol 885 ◽  
pp. 173498
Author(s):  
Guoqiang Zhang ◽  
Xiaohan Sun ◽  
Yuanjie Wen ◽  
A'xi Shi ◽  
Jianping Zhang ◽  
...  
Keyword(s):  
Farnesoid X Receptor

Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Thomas Vallim ◽  
Elizabeth Tarling ◽  
Tammy Kim ◽  
Mete Civelek ◽  
Angel Baldan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

2018 ◽  
Vol 38 (3) ◽  
pp. 356-370 ◽  
Author(s):  
A Gautam ◽  
YN Paudel ◽  
SAZ Abidin ◽  
U Bhandari
Keyword(s):  
Hepatic Injury ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Farnesoid X Receptor ◽  
Lipoprotein Cholesterol ◽  
In Vivo Studies ◽  
Low Density Lipoprotein Cholesterol ◽  
Pro Inflammatory Cytokines

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine- N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC–MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.

scholarly journals Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand

2020 ◽  
Author(s):  
Junhui Yu ◽  
Kui Yang ◽  
Jianbao Zheng ◽  
Wei Zhao ◽  
Xuejun Sun
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Farnesoid X Receptor ◽  
Colon Cancer Cells ◽  
Antitumor Effects ◽  
Colorectal Tumorigenesis ◽  
Tumor Inhibition ◽  
Combination Study

Abstract The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.

Transcriptional regulation of microRNA-126a by farnesoid X receptor in vitro and in vivo

2020 ◽  
Vol 42 (8) ◽  
pp. 1327-1336
Author(s):  
Yi Yan ◽  
Shichao Wang ◽  
Rui Wang ◽  
Puxuan Jiang ◽  
Yaqing Chen ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Farnesoid X Receptor

scholarly journals Mice Lacking FXR Are Susceptible to Liver Ischemia-Reperfusion Injury

2019 ◽  
Author(s):  
Yuxin Li ◽  
Rui Xu ◽  
Prahlad K. Rao ◽  
Charles K Gomes ◽  
E. Richard Moran ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Liver Weight ◽  
Farnesoid X Receptor ◽  
Tissue Ischemia ◽  
Stress Protection

AbstractActivation of bile acid (BA) receptor, farnesoid X receptor (FXR) has been shown to inhibit inflammatory responses and improve tissue ischemia-reperfusion injury (IRI). This study investigated the effect of FXR deficiency on liver IRI, using a liver warm IRI mouse model. We demonstrate that liver IRI resulted in decreased FXR expression in the liver of WT mice. FXR-/-mice displayed greater liver damage and inflammatory responses than WT mice, characterized by significant increases in liver weight, serum AST and ALT, hepatocyte apoptosis and liver inflammatory cytokines. Liver IRI increased expression of X box binding protein 1 (XBP1) and FGF21 in WT liver, but not in FXR-/- liver, which conversely increased CHOP expression, suggesting a loss of ER stress protection in the absence of FXR. FXR deficiency increased circulating total BAs and altered BA composition with reduced TUDCA and hepatic BA synthesis markers. FXR deficiency also reshaped gut microbiota composition with increased Bacteroidetes and Proteobacteria and decreased Firmicutes. Curiously, Bacteroidetes were positively and Firmicutes were negatively correlated with serum ALT levels. Administration of FXR agonist CDCA inhibited NF-κB activity and TNFα expression in vitro and improved liver IRI in vivo. Our findings demonstrate that FXR signaling plays an important role in the modulation of liver IRI.

Yangonin protects against cholestasis and hepatotoxity via activation of farnesoid X receptor in vivo and in vitro

2018 ◽  
Vol 348 ◽  
pp. 105-116 ◽  
Author(s):  
Xiaoguang Gao ◽  
Ting Fu ◽  
Changyuan Wang ◽  
Chenqing Ning ◽  
Kexin Liu ◽  
...  
Keyword(s):  
Farnesoid X Receptor

scholarly journals GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

2020 ◽  
Author(s):  
Jing Guo ◽  
Jianbao Zheng ◽  
Zhengshui Xu ◽  
Chenye Zhao ◽  
Kui Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Farnesoid X Receptor ◽  
Antitumor Effects ◽  
In Vivo Experiments ◽  
Stat3 Signaling ◽  
Synergistic Mechanism ◽  
Combination Study ◽  
Induced Apoptosis

Abstract Background Repeated and long-term oxaliplatin therapy leads to drug resistance and severe adverse events, which limit its clinical use. These difficulties highlight the importance of identifying potent and specific drug combinations to enhance the antitumor effects of oxaliplatin. The farnesoid X receptor (FXR) deficiency in colorectal cancer (CRC) suggests that restoring FXR function might be a promising strategy for CRC treatment.Methods A series of in vitro and in vivo experiments were conducted to assess the antitumor effect of the combination of oxaliplatin and FXR agonist GW4064 in CRC. The synergistic mechanism involved was explored.Results A drug combination study showed that the GW4064 acted synergistically with oxaliplatin in colon cancer cells. The combination of oxaliplatin plus GW4064 inhibited cell growth and colony formation, induced apoptosis and pyroptosis in vitro, and slowed tumor growth in vivo. Mechanistically, GW4064 enhanced the chemosensitivity of cells to oxaliplatin by inducing BAX/caspase-3/GSDME-mediated pyroptosis. Furthermore, the combination of oxaliplatin and GW4064 synergistically inhibited STAT3 signaling by restoring SHP expression.Conclusions Our study revealed that GW4064 could enhance the antitumor effects of oxaliplatin against CRC, which provides a novel therapeutic strategy based on a combinational approach for CRC treatment.

A naturally occurring FXR agonist, alisol B 23-acetate, protects against renal ischemia-reperfusion injury

2021 ◽  
Author(s):  
Zhi-Lin Luan ◽  
Wen-Hua Ming ◽  
Xiao-Wan Sun ◽  
Cong Zhang ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Farnesoid X Receptor ◽  
Site Directed Mutagenesis ◽  
Luciferase Assay ◽  
Naturally Occurring

The ligand-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating renal function. Activation of FXR by its specific agonists exerts renoprotective action in animals with acute kidney injury (AKI). In the present study, we aimed to identify naturally occurring agonists of FXR with potential as therapeutic agents in renal ischemia-perfusion injury (IRI). In vitro and in vivo FXR activation was determined by dual-luciferase assay, docking analysis, site-directed mutagenesis, and whole kidney transcriptome analysis. Wild-type (WT) and FXR knockout (FXR-/-) mice were used to determine the effect of potential FXR agonist on renal IRI. We found that alisol B 23-acetate (ABA), a major active triterpenoid extracted from Alismatis Rhizoma, a well-known traditional Chinese medicine, can activate renal FXR and induce FXR downstream gene expression in mouse kidney. ABA treatment significantly attenuated renal IR-induced AKI in WT mice but not in FXR-/- mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against IRI-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI.

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