Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity

Su, Qianqian; Tian, Yazhou; Liu, Zhenni; Ci, Leilei; Lv, Xiongwen

doi:10.1016/j.intimp.2018.11.012

Cited by 16 publications

(15 citation statements)

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“… de Campos et al (2012) found that P2X7R, when activated by ATP, upregulated pro-inflammatory mediator IL-1β and resulted in increased permeability in lymphocytes and macrophages in the MLN and colonic epithelial cells. Several papers highlight how P2X7R activation contributes to the loss of IEC barrier integrity through increased permeability of IECs ( de Campos et al, 2012 ), loss of tight junction proteins ( Diezmos et al, 2018 ; Su et al, 2019 ) and apoptosis of IECs ( Souza et al, 2012 ; Marques et al, 2014 ). This intestinal barrier dysfunction is important in the pathogenesis of IBD ( Coskun, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…Apart from its role in the inflammatory process and modulating immune responses, P2X7R has also been shown to have a role in GI malignancies ( Adinolfi et al, 2015 ; Hofman et al, 2015 ; Zhang et al, 2021 ), immune modulation ( Proietti et al, 2014 ; Perruzza et al, 2017 ; Liu and Kim, 2019 ; Perruzza et al, 2019 ; Proietti et al, 2019 ), metabolic regulation ( Bourzac et al, 2013 ; Arguin et al, 2017 ; Perruzza et al, 2017 ; Perruzza et al, 2019 ), ISR injury ( Palombit et al, 2019 ) and intestinal damage due to long-term morphine use ( Bhave et al, 2017 ), chronic binge alcohol feeding ( Su et al, 2019 ) and NSAID use ( Higashimori et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…In a chronic binge alcohol feeding model in mice by Su et al (2019) , 5% (vol/vol) ethanol was used for 10 days and controls were pair-fed. I.p.…”

Section: Discussionmentioning

confidence: 99%

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Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review

Cheng¹,

Zhang²,

Liu³

2021

Front. Pharmacol.

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Background: The role of purinergic P2X7 receptor (P2X7R) is of interest due to its involvement in inflammation and mediating immune cell responses. P2X7R is particularly implicated in the development of inflammatory bowel disease (IBD). However, the extent of the actions of P2X7R in the gastrointestinal (GI) system under physiological and pathophysiological conditions remains to be elucidated. This systematic review aimed to identify, summarize and evaluate the evidence for a critical role of P2X7R in the GI system.Methods: We searched PubMed, Embase and Scopus with search terms pertained to P2X7R in the GI system in disease or physiological state, including “P2X7 or P2X7 receptor or purinergic signaling” in combination with any of the terms “intestine or colon or gut or gastrointestinal,” “pathology or inflammation or disease or disorder,” and “physiology or expression.” Titles and abstracts were screened for potentially eligible full texts, and animal and human studies published in English were included in this study. Data were extracted from papers meeting inclusion criteria. Meta-analysis was not feasible given the study diversity.Results: There were 48 papers included in this review. We identified 14 experimental colitis models, three sepsis models and one ischemia-reperfusion injury model. Among them, 11 studies examined P2X7R in GI infections, six studies on immune cell regulation, four studies on GI inflammation, two studies on GI malignancies, three studies involving intestinal injury due to various causes, two studies on ATP-activated P2X7R in the GI system and two studies on metabolic regulation.Conclusion: Evidence supports P2X7R mediating inflammation and immune cell responses in GI inflammation, infections and injury due to IBD and other challenges to the intestinal wall. P2X7R inhibition by gene knockout or by application of P2X7R antagonists can reduce tissue damage by suppressing inflammation. P2X7R is also implicated in GI malignancies and glucose and lipid homeostasis. P2X7R blockade, however, did not always lead to beneficial outcomes in the various pathological models of study.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review

Cheng¹,

Zhang²,

Liu³

2021

Front. Pharmacol.

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“…P2X7R is primarily expressed on cells of hematopoietic, epithelial, mesenchymal and neural lineage, and plays major roles in immunity, neoplasia, inflammation and neurological functions ( 18 ). In addition, P2X7R is associated with lipid metabolism ( 19 ). P2X7R was also discovered to play an extensive role in controlling lipid storage and metabolism in vivo ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Purinergic 2X7 receptor is involved in adipogenesis and lipid degradation

Gong²,

2021

Exp Ther Med

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Obesity and dyslipidemia are two metabolic syndrome disorders that have serious effects on the health of patients. Purinergic 2X receptor ligand-gated ion channel 7 (P2X7R) has been reported to play a role in regulating lipid storage and metabolism. However, the role and potential mechanism of P2X7R in adipogenesis and lipid degradation remain unknown. In the present study, a mouse model of obesity was established by feeding mice a high-fat diet, and the 3T3-L1 cell line was used to analyze the function of P2X7R in vitro. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the expression levels of P2X7R, sterol regulatory element-binding protein 1 (SREBP1) and other associated transcription factors. Bioinformatics analysis was used to predict the potential target gene of P2X7R and a dual luciferase reporter assay was used to confirm this prediction. Oil Red O staining was used to evaluate the adipogenic capacity of preadipocytes. AdipoRed assay, cholesterol assay and a free glycerol reagent were used to measure the expression levels of triglyceride (TGs), total cholesterol (TC) and glycerin, respectively. The results indicated that P2X7R was highly expressed in obese mice and that it was involved in adipogenic differentiation in vitro. SREBP1 enhanced the transcription activities of P2X7R to promote its expression. Inhibition of P2X7R significantly reduced the adipogenic capacity of preadipocytes, decreased the expression levels of adipogenesis-associated transcription factors (peroxisome proliferator-activated receptor γ, CCAAT-enhancer-binding protein α and fatty-acid-binding protein 4), enhanced the expression levels of lipolytic enzymes (adipose triglyceride lipase, phosphorylated hormone-sensitive lipase and monoacylglycerol lipase) and regulated the expression of TG, TC and glycerin in mature 3T3-L1 cells. These effects were reversed by a small interfering RNA targeting Wnt3a. Therefore, the results suggested that P2X7R, the transcription activities of which were regulated by SREBP1, regulated adipogenesis and lipid degradation by targeting SREBP1, indicating its potential effects on obesity-associated metabolism.

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“…Its receptor affects lipid metabolism [6][7][8][9] by activating the dangerous molecule ATP derived from liver cells caused by alcohol [10]. Recent studies have found that P2 × 7R mediates the activation of NLRP3 in amemome and lipid deposition in hepatocytes, P2 × 7R blocker alleviates alcohol-induced steatosis and intestinal ora changes via MEK1/2-ERK1/2 signaling [11]. Moreover, P2 × 7R is a vital target in hepatitis-induced oxidative stressmediated autophagy, but the role of P2 × 7R in alcoholic liver remains to be further studied.…”

Section: Introductionmentioning

confidence: 99%

Penthorum Chinense Pursh Protects Liver From Alcohol-induced Steatosis in Zebrafish by Mechanisms Including Inhibition of Oxidative Stress and Increase in Autophagy

Zhao

Zhou

Deng

et al. 2020

Preprint

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BackgroundAs an ATP-gated ion channel, P2X7 receptor (P2X7R) affects lipid metabolism by activating the dangerous molecule ATP derived from liver cells caused by alcohol. Penthorum chinense Pursh (PCP), known as “shenxiancao”, plays a significant role in treating liver disease among Miao people. We first investigated whether liver protection mechanism of PCP mediated by P2X7R. MethodsFirst, treatment of zebrafish transgenic (fabp10: EGFP) larvae with different concentrations of PCP after 48 h at 3 dpf, then soaked in 350 mmol/L ethanol for 32 h. Subsequently the ameliorative effect of PCP in zebrafish with alcoholic hepatosteatosis was studied. In addition, gene expression related to lipid metabolism, oxidative stress, and autophagy was detected from the mRNA level by RT-qPCR and related proteins were measured by Western blot. Then, larvae were stimulated with ATP alone to explore whether PCP was the target of P2X7R.ResultsPCP significantly improved liver function and lipid deposition in zebrafish with alcoholic hepatosteatosis, and regulated the expression of SREBP1, CHREBP and FAS by elevating LKB1 and AMPK, thereby inhibiting the synthesis of fatty acids. Also, SIRT1 was suppressed in the model group, while PCP upregulated the expression. Inecreased expression of PPARα, decreased PPARγ, and CPT1 then promoted the oxidation of fatty acids. PCP dose-dependently decreased intracellular ROS production in zebrafish, then reduced MDA activity elevation and increased GSH, CAT and SOD levels. The specific mechanism may be realized by up-regulating the antioxidant pathway of Keap1/Nrf2 and down-regulating the autophagy pathway of PI3K/Akt/mTOR to regulate lipid metabolism. After ATP stimulation, P2X7R is further activated, which in turn regulated Keap1/Nrf2 and mTOR/PI3K/Akt mRNA expression, while PCP reversed these changes.ConclusionsPCP may be a target of P2X7R involvement in the regulation of this mechanism through up-regulation of the antioxidant pathway of Keap1/Nrf2 and down-regulation of the autophagic pathway of mTOR/ PI3K/Akt to regulate lipid metabolism, suggesting that blocking P2X7R is an emerging strategy for the therapy of ALD.

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Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity

Cited by 16 publications

References 38 publications

Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review

Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review

Purinergic 2X7 receptor is involved in adipogenesis and lipid degradation

Penthorum Chinense Pursh Protects Liver From Alcohol-induced Steatosis in Zebrafish by Mechanisms Including Inhibition of Oxidative Stress and Increase in Autophagy

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