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.

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.

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 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.

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.

Nuclear receptors and hepatic lipidogenic enzyme response to a dyslipidemic sucrose-rich diet and its reversal by fish oil n-3 polyunsaturated fatty acids

2010 ◽  
Vol 298 (3) ◽  
pp. E429-E439 ◽  
Author(s):  
Gustavo J. Hein ◽  
Ana M. Bernasconi ◽  
Mauro A. Montanaro ◽  
Magali Pellon-Maison ◽  
Gabriela Finarelli ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Lipid Metabolism ◽  
Fish Oil ◽  
Nuclear Receptors ◽  
Peroxisome Proliferator ◽  
Cod Liver Oil ◽  
Hepatic Enzymes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver X Receptor Α ◽  
Glucose 6 Phosphate Dehydrogenase

A sucrose-rich diet (SRD), compared with a starch diet, induces time-dependent metabolic disorders and insulin resistance with hypertriglyceridemia, similar to type 2 diabetes. In this study, we examined the effect of SRD, after 8 mo, on nuclear receptors peroxisome proliferator-activated receptor-α (PPARα), and liver X receptor-α (LXRα), stearoyl-CoA desaturase-1 (SCD-1), and Δ6 and Δ5 desaturases mRNA and activity, hepatic enzymes involved in lipid metabolism, and fatty acid (FA) composition as well as the reversal produced by cod liver oil. SRD induced triglyceride increase in plasma and liver, increasing the anabolic FA synthase, malic enzyme, and glucose-6-phosphate dehydrogenase, but not the prooxidative enzymes FA oxidase and carnitine palmitoyltransferase I, and correspondingly decreased PPARα and increased LXRα expressions. Results suggest a contribution of both nuclear receptors' interaction on these enzymatic activities. SRD depressed SCD-1 without altering oleic acid proportion and increased Δ6 and Δ5 desaturases and the proportion of n-6 arachidonic acid. Therefore, the data do not support that SRD hypertriglyceridemia is produced by increased SCD-1-dependent oleic acid biosynthesis. The administration of 7% cod liver oil for 2 mo depressed LXRα, enhancing PPARα in control and SRD-fed rats, reversing the activity of the hepatic enzymes involved in lipid metabolism and therefore the hyperlipidemia produced by the SRD. Fish oil increased n-3 PUFA and depressed n-6 PUFA of liver lipids without altering the 18:1/18:0 ratio, suggesting that its effects were produced mainly by competition of dietary n-6 and n-3 FA and not through desaturase activity modification.

scholarly journals Gene Expression Profiling Reveals That PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

2019 ◽  
Author(s):  
Sharon Ann Barretto ◽  
Frederic Lasserre ◽  
Anne Fougerat ◽  
Lorraine Smith ◽  
Tiffany Fougeray ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Target Genes ◽  
Pregnane X Receptor ◽  
Alpha Activity ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Metabolizing Enzymes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Xenobiotic Metabolizing Enzymes ◽  
Triglyceride Accumulation

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes mostly xenobiotic metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.

scholarly journals Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

2017 ◽  
Author(s):  
Husna Yetti ◽  
Hisao Naito ◽  
Yuan Yuan ◽  
Xiaofang Jia ◽  
Yumi Hayashi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Pregnane X Receptor ◽  
Mature Female ◽  
Farnesoid X Receptor ◽  
Detoxification Enzymes ◽  
Cytochrome P450 Enzymes ◽  
High Fat ◽  
Expression Levels

During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstene receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.

scholarly journals PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

2020 ◽  
Vol 21 (6) ◽  
pp. 2061 ◽  
Author(s):  
Yaping Wang ◽  
Takero Nakajima ◽  
Frank J. Gonzalez ◽  
Naoki Tanaka
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Cancer ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Regulators

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.

scholarly journals Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

2019 ◽  
Vol 20 (15) ◽  
pp. 3767 ◽  
Author(s):  
Sharon Ann Barretto ◽  
Frédéric Lasserre ◽  
Anne Fougerat ◽  
Lorraine Smith ◽  
Tiffany Fougeray ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Target Genes ◽  
Pregnane X Receptor ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Metabolizing Enzymes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Xenobiotic Metabolizing Enzymes ◽  
Triglyceride Accumulation ◽  
Transcriptomic Signature

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs. Pxr-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes, mostly xenobiotic-metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which was the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.

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