The Therapeutic Role of Xenobiotic Nuclear Receptors Against Metabolic Syndrome

2019 ◽  
Vol 20 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Shuqi Pu ◽  
Xiaojie Wu ◽  
Xiaoying Yang ◽  
Yunzhan Zhang ◽  
Yunkai Dai ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Metabolic Diseases ◽  
Constitutive Androstane Receptor ◽  
Therapeutic Targets ◽  
Pregnane X Receptor ◽  
Original Data ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism

Background: Diabetes, with an increased prevalence and various progressive complications, has become a significant global health challenge. The concrete mechanisms responsible for the development of diabetes still remain incompletely unknown, although substantial researches have been conducted to search for the effective therapeutic targets. This review aims to reveal the novel roles of Xenobiotic Nuclear Receptors (XNRs), including the Peroxisome Proliferator-Activated Receptor (PPAR), the Farnesoid X Receptor (FXR), the Liver X Receptor (LXR), the Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR), in the development of diabetes and provide potential strategies for research and treatment of metabolic diseases. Methods: We retrieved a large number of original data about these five XNRs and organized to focus on their recently discovered functions in diabetes and its complications. Results: Increasing evidences have suggested that PPAR, FXR, LXR ,PXR and CAR are involved in the development of diabetes and its complications through different mechanisms, including the regulation of glucose and lipid metabolism, insulin and inflammation response and related others. Conclusion: PPAR, FXR, LXR, PXR, and CAR, as the receptors for numerous natural or synthetic compounds, may be the most effective therapeutic targets in the treatment of metabolic diseases.

Nuclear Receptors in Acute and Chronic Cholestasis

2015 ◽  
Vol 33 (3) ◽  
pp. 357-366 ◽  
Author(s):  
Ester Gonzalez-Sanchez ◽  
Delphine Firrincieli ◽  
Chantal Housset ◽  
Nicolas Chignard
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptors ◽  
Energy Homeostasis ◽  
Therapeutic Targets ◽  
Pregnane X Receptor ◽  
Estrogen Receptor Α ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Hepatic Expression ◽  
The Impact

Background: Nuclear receptors (NRs) form a family of 48 members. NRs control hepatic processes such as bile acid homeostasis, lipid metabolism and mechanisms involved in fibrosis and inflammation. Due to their central role in the regulation of hepatoprotective mechanisms, NRs are promising therapeutic targets in cholestatic disorders. Key Messages: NRs can be classified into five different physiological clusters. NRs from the ‘bile acids and xenobiotic metabolism' and from the ‘lipid metabolism and energy homeostasis' clusters are strongly expressed in the liver. Furthermore, NRs from these clusters, such as farnesoid X receptor α (FXRα), pregnane X receptor (PXR) and peroxisome proliferator-activated receptors (PPARs), have been associated with the pathogenesis and the progression of cholestasis. The latter observation is also true for vitamin D receptor (VDR), which is barely detectable in the whole liver, but has been linked to cholestatic diseases. Involvement of VDR in cholestasis is ascribed to a strong expression in nonparenchymal liver cells, such as biliary epithelial cells, Kupffer cells and hepatic stellate cells. Likewise, NRs from other physiological clusters with low hepatic expression, such as estrogen receptor α (ERα) or reverse-Erb α/β (REV-ERB α/β), may also control pathophysiological processes in cholestasis. Conclusions: In this review, we will describe the impact of individual NRs on cholestasis. We will then discuss the potential role of these transcription factors as therapeutic targets.

Cytosol-nucleus traffic and colocalization with FXR of conjugated bile acids in rat hepatocytes

2008 ◽  
Vol 295 (1) ◽  
pp. G54-G62 ◽  
Author(s):  
Maria J. Monte ◽  
Ruben Rosales ◽  
Rocio I. R. Macias ◽  
Valeria Iannota ◽  
Almudena Martinez-Fernandez ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Bile Acids ◽  
Nuclear Receptors ◽  
Rat Hepatocytes ◽  
Nuclear Volume ◽  
Farnesoid X Receptor ◽  
Nuclear Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rat Liver Cells

Bile acids (BAs) are natural ligands of nuclear receptors, in particular farnesoid X receptor (FXR). Whether, in addition to protein-mediated cytosolic-nuclear BA translocation, other mechanisms are involved in the access of BAs to nuclear FXR was investigated. When rat hepatocytes were incubated with radiolabeled taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and tauroursodeoxycholic acid, their nuclear accumulation was proportional to their intracellular levels. With the use of flow cytometry analysis, the accumulation by nuclei isolated from rat liver cells was found to differ for several fluorescent compounds of similar molecular weight and different charge, including fluorescein-tagged BAs [cholylglycyl amidofluorescein (CGamF), ursodeoxycholylglycyl amidofluorescein, or chenodeoxycholylglycyl amidofluorescein]. When we varied nuclear volume by incubation with different sucrose concentrations, a similar relationship between nuclear volume and content of FITC and 4-kDa FITC-dextran was found. In contrast, this relationship was markedly lower for CGamF. Confocal microscopy studies revealed that fluorescein-tagged BAs, but also FITC or 10-kDa FITC-dextran were found in the nuclear envelope and concentrated in regions where DNA was less densely packed. In contrast to the cytosolic subcellular localization of peroxisome proliferator-activated receptor-α, FXR and nucleolin (a marker of transcriptional active chromatin) were also localized by immunoreactivity in these intranuclear regions. In conclusion, although intranuclear levels of small organic molecules including conjugated BAs depend on their concentrations in the extranuclear space, the existence of certain molecular selectivity (not strictly dependent on molecular weight or charge) suggests that, in addition to simple diffusional exchange, other mechanisms may be also involved in determining their overall nuclear content in regions where these compounds coincide and may interact with nuclear receptors such as FXR.

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

2017 ◽  
Vol 35 (3) ◽  
pp. 203-209 ◽  
Author(s):  
Kang Ho Kim ◽  
David D. Moore
Keyword(s):  
Energy Balance ◽  
Nuclear Receptors ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Post Translational Modifications ◽  
Fed State ◽  
Fasted State ◽  
Opposing Effects ◽  
Metabolic Output

Background: The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. Conclusions: FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and that these pathways will in turn interface with other well-known nutrient-responsive mechanisms of energy control.

scholarly journals Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan differs from mercury chloride and methylmercury on hepatic cytochrome P450 in mice

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 203
Author(s):  
Yu Nie ◽  
Shang-Fu Xu ◽  
Yan-Liu Lu ◽  
Xiu-Rong Zhao ◽  
Cen Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Western Blot ◽  
Mrna Expression ◽  
Nuclear Receptors ◽  
Pregnane X Receptor ◽  
Gastrointestinal Diseases ◽  
Farnesoid X Receptor ◽  
Tibetan Medicine ◽  
Mercury Chloride ◽  
Peroxisome Proliferator

Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) is a famous Tibetan medicine for treating cardiovascular and gastrointestinal diseases.  We have shown that 70W protected against CCl4 hepatotoxicity.  CCl4 is metabolized via cytochrome P450 (CYP) to produce reactive metabolites. Whether 70W has any effect on CYPs is unknown and such effects should be compared with mercury compounds for safety evaluation.   Methods: Mice were given clinical doses of 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), and compared to HgCl2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for seven days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic mRNA expression of Cyp1a2, Cyp2b10, Cyp3a11, Cyp4a10 and Cyp7a1, and corresponding nuclear receptors [aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα); farnesoid X receptor (FXR)]. In comparison, HgCl2 and MeHg increased mRNA expression of Cyp1a2, Cyp2b10, Cyp4a10 and Cyp7a1 except for Cyp3a11, and corresponding nuclear receptors except for PXR. Western-blot confirmed mRNA results, showing increases in CYP1A2, CYP2B1, CYP2E1, CYP4A and CYP7A1 by HgCl2 and MeHg only, and all treatments had no effects on CYP3A. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs and corresponding nuclear receptors, while HgCl2 and MeHg produced significant effects.  Thus, the use of total Hg content to evaluate the safety of HgS-containing 70W is inappropriate.

scholarly journals High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jill A. Franzosa ◽  
Jessica A. Bonzo ◽  
John Jack ◽  
Nancy C. Baker ◽  
Parth Kothiya ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Screening Program ◽  
Cell Model ◽  
Quantitative Polymerase Chain Reaction ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Molecular Signaling ◽  
Peroxisome Proliferator Activated Receptor

AbstractThe ToxCast in vitro screening program has provided concentration-response bioactivity data across more than a thousand assay endpoints for thousands of chemicals found in our environment and commerce. However, most ToxCast screening assays have evaluated individual biological targets in cancer cell lines lacking integrated physiological functionality (such as receptor signaling, metabolism). We evaluated differentiated HepaRGTM cells, a human liver-derived cell model understood to effectively model physiologically relevant hepatic signaling. Expression of 93 gene transcripts was measured by quantitative polymerase chain reaction using Fluidigm 96.96 dynamic arrays in response to 1060 chemicals tested in eight-point concentration-response. A Bayesian framework quantitatively modeled chemical-induced changes in gene expression via six transcription factors including: aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, androgen receptor, and peroxisome proliferator-activated receptor alpha. For these chemicals the network model translates transcriptomic data into Bayesian inferences about molecular targets known to activate toxicological adverse outcome pathways. These data also provide new insights into the molecular signaling network of HepaRGTM cell cultures.

scholarly journals Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan (Rannasangpei) differs from mercury chloride and methylmercury on hepatic cytochrome P450

2020 ◽  
Author(s):  
Yu Nie ◽  
Shang-Fu Xu ◽  
Yan-Liu Lu ◽  
Xiu-Rong Zhao ◽  
Cen Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Pregnane X Receptor ◽  
Gastrointestinal Diseases ◽  
Farnesoid X Receptor ◽  
Tibetan Medicine ◽  
Mercury Chloride ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mercury Compounds ◽  
Protein Expressions

Abstract Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei ) is a famous Tibetan medicine for cardiovascular and gastrointestinal diseases. We have shown that 70W protected against CCl 4 hepatotoxicity. CCl 4 is metabolized via cytochrome P450 (CYP450) to produce reactive metabolites. Whether 70W has any effect on CYP450 is unknown and such effects should be compared with mercury compounds for safety evaluation. Methods: Mice were given 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), HgCl 2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for 7 days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic Aryl hydrocarbon receptor (AhR) and CYP1A2, but HgCl 2 and MeHg increased Cyp1a2 mRNA and CYP1A2 protein levels;70W and Zuotai had no effects on constitutive androstane receptor (CAR) ,CYP2B andCYP2E1 expressions, but HgCl 2 increased CAR and Cyp2b10 mRNA, HgCl 2 and MeHg increased CYP2B and CYP2E1 protein expressions; 70W and mercury compounds had no apparent effects on the expression of pregnane X receptor (PXR) and Cyp3a11 mRNA, as well as CYP3A proteins. 70W and mercury compounds had no apparent effects on the expression of peroxisome proliferator-activated receptor alpha (PPARα) and CYP4A; but HgCl 2 tended to increase Cyp4a10 mRNA and CYP4A protein expressions. 70W and Zuotai had no apparent effects on the expression of farnesoid X receptor (FXR) and Cyp7a1 , while HgCl 2 and MeHg increased CYP7A1 expression. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs, and the effects of 70W and Zuotai on CYP and corresponding nuclear receptors are different from HgCl 2 and MeHg.

scholarly journals Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan differs from mercury chloride and methylmercury on hepatic cytochrome P450 in mice

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 203
Author(s):  
Yu Nie ◽  
Shang-Fu Xu ◽  
Yan-Liu Lu ◽  
Xiu-Rong Zhao ◽  
Cen Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Western Blot ◽  
Mrna Expression ◽  
Nuclear Receptors ◽  
Pregnane X Receptor ◽  
Gastrointestinal Diseases ◽  
Farnesoid X Receptor ◽  
Tibetan Medicine ◽  
Mercury Chloride ◽  
Peroxisome Proliferator

Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) is a famous Tibetan medicine for treating cardiovascular and gastrointestinal diseases.  We have shown that 70W protected against CCl4 hepatotoxicity.  CCl4 is metabolized via cytochrome P450 (CYP) to produce reactive metabolites. Whether 70W has any effect on CYPs is unknown and such effects should be compared with mercury compounds for safety evaluation.   Methods: Mice were given clinical doses of 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), and compared to HgCl2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for seven days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic mRNA expression of Cyp1a2, Cyp2b10, Cyp3a11, Cyp4a10 and Cyp7a1, and corresponding nuclear receptors [aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα); farnesoid X receptor (FXR)]. In comparison, HgCl2 and MeHg increased mRNA expression of Cyp1a2, Cyp2b10, Cyp4a10 and Cyp7a1 except for Cyp3a11, and corresponding nuclear receptors except for PXR. Western-blot confirmed mRNA results, showing increases in CYP1A2, CYP2B1, CYP2E1, CYP4A and CYP7A1 by HgCl2 and MeHg only, and all treatments had no effects on CYP3A. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs and corresponding nuclear receptors, while HgCl2 and MeHg produced significant effects.  Thus, the use of total Hg content to evaluate the safety of HgS-containing 70W is inappropriate.

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