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Zinc lactate alleviates oxidative stress by modulating crosstalk between constitutive androstane receptor signaling pathway and gut microbiota profile in weaned piglets

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Animal Nutrition 2024年第1期16卷 23-33页

作者： Wenjie Tang Xuan Xiang Houfu Wang Wentao Zhou Liuqin He Yulong Yin Tiejun Li College of Animal Science and Technology Hunan Agricultural University Sichuan Academy of Animal Sciences Animal Breeding and Genetics Key Laboratory of Sichuan Province Livestock and Poultry Biological Products Key Laboratory of Sichuan Province Sichuan Animtech Feed Co. Ltd Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production Institute of Subtropical Agriculture Chinese Academy of Sciences College of Advanced Agricultural Science University of Chinese Academy of Sciences Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation Laboratory of Animal Nutrition and Human Health College of Life Sciences Hunan Normal University

This study aimed to determine the regulatory mechanism of dietary zinc lactate (ZL) supplementation on intestinal oxidative stress damage in a paraquat (PQ)-induced piglet model. Twenty-eight piglets (mean body weight 9.51±0.23 kg) weaned at 28 d of age were randomly divided into control, ZL, PQ, and ZL+PQ groups (n=7 in each group). The ZL-supplemented diet had little effect on growth performance under normal physiological conditions. However, under PQ challenge, ZL supplementation significantly improved average daily gain (Pconstitutive androstane receptor (CAR) signaling (P<0.01) in PQ-induced piglets and altered the structure of the gut microbiota, especially by significantly increasing the abundance of beneficial gut microbes, including UCG＿002, Ruminococcus, Rikenellaceae＿RC9＿gut＿group, Christensenellaceae＿R＿7＿group, Treponema, unclassified＿Christensenellaceae, and unclassified＿Erysipelotrichaceae (P <0.05). These data reveal that pre-administration of ZL to piglets can suppress intestinal oxidative stress by improving antioxidant and anti-inflammatory capacity and regulating the crosstalk between CAR signaling and gut microbiota.

关键词： Zinc lactate Intestinal barrier Oxidative stress Inflammation constitutive androstane receptor Gut microbiota

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constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation

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Acta Pharmaceutica Sinica B 2021年第3期11卷 727-737页

作者： Yue Gao Shicheng Fan Hua Li Yiming Jiang Xinpeng Yao Shuguang Zhu Xiao Yang Ruimin Wang Jianing Tian Frank JGonzalez Min Huang Huichang Bi Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Hepatic Surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510006China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNIHBethesdaMD 20892USA

The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor superfamily.It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration.TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice.Hepatocytes enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.

关键词： constitutive androstane receptor Nuclear receptors Hepatomegaly Liver enlargement Liver regeneration Yes-associated protein Proteineprotein interaction Partial hepatectomy

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pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

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World Journal of Gastroenterology 2017年第42期23卷 7519-7530页

作者： Daniela Gabbia Arianna Dalla Pozza Laura Albertoni Roberta Lazzari Giorgia Zigiotto Maria Carrara Vincenzo Baldo Tatjana Baldovin Annarosa Floreani Sara De Martin Department of Pharmaceutical and Pharmacological Sciences University of Padova Department of Medicine General Pathology and Cytopathology UnitUniversity of Padova Department of Cardiac Thoracicand Vascular SciencesHygiene and Public Health UnitUniversity of Padova Department of Surgery Oncology and GastroenterologyUniversity of Padova

AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P < 0.01). At variance, m RNA and protein expression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.

关键词： Cholestasis CYP3A Drug metabolism Pregnane X receptor constitutive androstane receptor

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Signaling control of the constitutive androstane receptor （CAR）

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Protein & Cell 2014年第2期5卷 113-123页

作者： Hui Yang Hongbing Wang Department of Pharmaceutical Sciences University of Maryland School of Pharmacy 20 Penn Street Baltimore MD 21201 USA

The constitutive androstane receptor （CAR, NRll3） plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent （indirect） mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mecha- nisms yet to be fully understood. Accumulating evi- dence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be func- tionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our under- standing of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation.

关键词： constitutive androstane receptor nucleartranslocation phosphorylation signaling regulation

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Atypical functions of xenobiotic receptors in lipid and glucose metabolism

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Medical Review 2022年第6期2卷 611-624页

作者： Jingyuan Wang Peipei Lu Wen Xie Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPAUSA Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Department of Pharmacology and Chemical Biology University of PittsburghPittsburghPA 15261USA

Xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors,the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics.Emerging evidence suggests that“xenobiotic receptors”also have diverse endobiotic functions,including their effects on lipid metabolism and energy metabolism.Dyslipidemia is a major risk factor for cardiovascular disease,diabetes,obesity,metabolic syndrome,stroke,nonalcoholic fatty liver disease(NAFLD),and nonalcoholic steatohepatitis(NASH).Understanding the molecular mechanism by which transcriptional factors,including the xenobiotic receptors,regulate lipid homeostasis will help to develop preventive and therapeutic approaches.This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors:aryl hydrocarbon receptor(AhR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR),in metabolic disorders,with a particular focus on their effects on lipid and glucose metabolism.Collectively,the literatures suggest the potential values of AhR,PXR and CAR as therapeutic targets for the treatment of NAFLD,NASH,obesity and diabetes,and cardiovascular diseases.

关键词： aryl hydrocarbon receptor constitutive androstane receptor lipid metabolism pregnane X receptor xenobiotic receptors

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