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Article(id=1208491435180012120, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208491433464541768, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2021-0493, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1617552000000, receivedDateStr=2021-04-05, revisedDate=1618416000000, revisedDateStr=2021-04-15, acceptedDate=null, acceptedDateStr=null, onlineDate=1766056410832, onlineDateStr=2025-12-18, pubDate=1620748800000, pubDateStr=2021-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766056410832, onlineIssueDateStr=2025-12-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766056410832, creator=13701087609, updateTime=1766056410832, updator=13701087609, issue=Issue{id=1208491433464541768, tenantId=1146029695717560320, journalId=1189982191388893191, year='2021', volume='56', issue='5', pageStart='1201', pageEnd='1512', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766056410422, creator=13701087609, updateTime=1766137182836, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208830217578214182, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208491433464541768, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208830217578214183, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208491433464541768, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1360, endPage=1368, ext={EN=ArticleExt(id=1208491435565888103, articleId=1208491435180012120, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Dynamic change of hepatocyte during PXR-induced liver enlargement, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Pregnane X receptor (PXR), a member of nuclear receptor superfamily, plays an important role in xenobiotic and endogenous metabolism, endocrine balance, and cell proliferation, etc. Previous study has shown that pregnenolone 16α-carbonitrile (PCN), a mouse PXR agonist, could induce liver enlargement. And we found that the change in hepatocytes exhibits regional distribution characteristics: hepatocyte enlargement occurs around the central vein (CV) area, while hepatocyte proliferation occurs around the portal vein (PV) area. In this study, the dynamic changes of hepatocytes during PXR-induced liver enlargement were determined. Serum and liver samples from male C57BL/6 mice were collected for biochemical and pathological analysis after PCN treatment for 1, 2, 3, 5 days, respectively. The animal experiment was approved by the Animal Ethics Committee of Sun Yat-Sen University. The results showed that with the increase in the PCN treatment days, the feature of this regional change of hepatocyte around the CV and PV areas became more and more obvious. At the same time, the factors related to hepatocyte enlargement, such as the expression of PXR downstream genes and the hepatic content of triglyceride (TG), has gradually increased. The upregulation of proliferation-related proteins and downregulation of cyclin-dependent kinases inhibitor proteins were observed in the early stage of PCN treatment, suggesting that hepatocyte proliferation occurs earlier than hepatocyte enlargement during PXR-induced liver enlargement. This study reveals the dynamic change of hepatocytes during PXR-induced liver enlargement and provides a new insight in liver enlargement promoted via PXR activation.

, correspAuthors=Hui-chang BI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2021 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jia-ning TIAN, Rui-min WANG, Xiao YANG, Jie YANG, Yi-fei ZHANG, Min HUANG, Hui-chang BI), CN=ArticleExt(id=1208491438111830709, articleId=1208491435180012120, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=PXR所致小鼠肝增大的肝细胞动态变化研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

孕烷X受体（pregnane X receptor，PXR）是核受体超家族成员，在内外源物质代谢、内分泌平衡和细胞增殖等过程中发挥重要调控作用。本课题组前期研究表明，给予PXR鼠源激动剂孕烯醇酮16α-腈（pregnenolone 16α-carbonitrile，PCN）可致小鼠肝增大，并发现此过程肝细胞的变化具有区域性分布的特征：中央静脉（central vein，CV）区肝细胞增大，而门静脉（portal vein，PV）区肝细胞增殖。本研究旨在评估PXR所致肝增大过程肝细胞动态变化的特点。雄性C57BL/6小鼠给予PCN后1、2、3、5天后采集血清及肝脏样本进行生化和病理检测，此动物实验经由中山大学动物伦理委员会批准。结果表明，随着给药时间的延长，小鼠CV区肝细胞体积逐渐增大，PV区肝细胞增殖增加；同时肝细胞增大相关因素如PXR下游细胞色素P450（cytochrome P450，CYP450）代谢酶和转运体的表达以及肝脏甘油三酯（triglyceride，TG）含量均逐渐增加，而肝细胞增殖的增殖相关蛋白的上调以及细胞周期抑制蛋白的下调则在给药初期即有显著变化，提示在PXR所致小鼠肝增大过程中肝细胞增殖的发生早于肝细胞增大。本研究阐明了PXR所致肝增大过程中肝细胞增大与增殖的动态变化，为PXR促进肝增大的研究提供新数据和新观点。

, correspAuthors=毕惠嫦, authorNote=null, correspAuthorsNote=
*毕惠嫦, Tel: 86-20-39943470, Fax: 86-20-39943000, E-mail:
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Drug Metab Dispos, 2016, 44: 647-652., articleTitle=Schisandra sphenanthera extract facilitates liver regeneration after partial hepatectomy in mice, refAbstract=null), Reference(id=1208491449218347558, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, doi=10.1080/01926230490440934, pmid=null, pmcid=null, year=2004, volume=32, issue=null, pageStart=393, pageEnd=401, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=Allen DG, Pearse G, Haseman JK, journalName=Toxicol Pathol, refType=null, unstructuredReference= Allen DG , Pearse G , Haseman JK et al . Prediction of rodent carcinogenesis: an evaluation of prechronic liver lesions as forecasters of liver tumors in NTP carcinogenicity studies[J]. Toxicol Pathol, 2004, 32: 393-401., articleTitle=Prediction of rodent carcinogenesis: an evaluation of prechronic liver lesions as forecasters of liver tumors in NTP carcinogenicity studies, refAbstract=null), Reference(id=1208491449348371000, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, doi=10.1007/s00204-020-02955-4, pmid=null, pmcid=null, year=2021, volume=95, issue=null, pageStart=1089, pageEnd=1102, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=Shizu R, Ishimura M, Nobusawa S, journalName=Arch Toxicol, refType=null, unstructuredReference= Shizu R , Ishimura M , Nobusawa S et al . The influence of the long-term chemical activation of the nuclear receptor pregnane X receptor (PXR) on liver carcinogenesis in mice[J]. Arch Toxicol, 2021, 95: 1089-1102., articleTitle=The influence of the long-term chemical activation of the nuclear receptor pregnane X receptor (PXR) on liver carcinogenesis in mice, refAbstract=null), Reference(id=1208491449465811529, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, doi=10.3390/cells9112395, pmid=null, pmcid=null, year=2020, volume=9, issue=null, pageStart=2395, pageEnd=null, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=Daujat-Chavanieu M, Gerbal-Chaloin S, journalName=Cells, refType=null, unstructuredReference= Daujat-Chavanieu M , Gerbal-Chaloin S . Regulation of CAR and PXR expression in health and disease[J]. Cells, 2020, 9: 2395., articleTitle=Regulation of CAR and PXR expression in health and disease, refAbstract=null)], funds=[Fund(id=1208491444835299529, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, awardId=81973392, language=CN, fundingSource=国家自然科学基金资助项目(81973392), fundOrder=null, country=null), Fund(id=1208491444935962838, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, awardId=82025034, language=CN, fundingSource=国家自然科学基金资助项目(82025034), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1208491438426403528, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, xref=null, ext=[AuthorCompanyExt(id=1208491438434792137, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, companyId=1208491438426403528, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Lab of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China), AuthorCompanyExt(id=1208491438443180746, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, companyId=1208491438426403528, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 药物代谢与药动学实验室, 广东 广州 510006)])], figs=[ArticleFig(id=1208491442872365081, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=O/4gV03k+HTtsoXIe7r7UA==, figureFileBig=A7DLNC8Djqp9ZUYZJFii4Q==, tableContent=null), ArticleFig(id=1208491442989805602, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Figure 1, caption= The dynamic change of pregnenolone 16<i>α</i>-carbonitrile (PCN)-induced liver enlargement in mice. A: Morphological pictures of livers of the vehicle mice and the PCN-treated mice; B: Liver/body weight ratios. Data are presented as mean ± SD (<i>n</i> = 5). <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> the vehicle group , figureFileSmall=O/4gV03k+HTtsoXIe7r7UA==, figureFileBig=A7DLNC8Djqp9ZUYZJFii4Q==, tableContent=null), ArticleFig(id=1208491443237269567, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=F++7b7tHHpmpQucq5J3AYw==, figureFileBig=tnva8tkt6ARDjLOZyhGJqA==, tableContent=null), ArticleFig(id=1208491443363098698, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Figure 2, caption= PCN treatment induces physiological liver enlargement. A: H&E staining of liver section; B: Serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels in different groups; C: RT-qPCR analysis of pro-inflammatory cytokines <i>Tnfα</i>, <i>Ifnγ</i>, <i>Il6</i> in different groups. Data are presented as mean ± SD (<i>n</i> = 5 or 6). <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> the vehicle group , figureFileSmall=F++7b7tHHpmpQucq5J3AYw==, figureFileBig=tnva8tkt6ARDjLOZyhGJqA==, tableContent=null), ArticleFig(id=1208491443480539222, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=I2ADcWX3+tiTViwp0pAtGQ==, figureFileBig=ep4N94Tp2p070RSBg/Agzw==, tableContent=null), ArticleFig(id=1208491443602174046, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Figure 3, caption= Hepatocyte size around the central vein (CV) area was gradually increased after PCN treatment. A: Immunohistochemical of <i>β</i>-catenin (CTNNB1) around the CV and portal vein (PV) area; B: Quantification of hepatocyte size. The yellow dashed line represents the average of hepatocyte size of the vehicle group; C: Proportion of hepatocyte size increased compared to the vehicle group. Data are presented as mean ± SD (<i>n</i> = 6). <sup>**</sup><i>P</i> < 0.01, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> the CV area of the vehicle group; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>####</sup><i>P</i> < 0.000 1 <i>vs</i> the PV area of the PCN group , figureFileSmall=I2ADcWX3+tiTViwp0pAtGQ==, figureFileBig=ep4N94Tp2p070RSBg/Agzw==, tableContent=null), ArticleFig(id=1208491443728003177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=/DN4v1gcW3Ix/MlelD4VsA==, figureFileBig=kg4f2HBohRvGzO0/b8K5/Q==, tableContent=null), ArticleFig(id=1208491443828666484, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Figure 4, caption= Hepatocyte proliferation around the PV area was promoted after PCN treatment. A: Immunohistochemical of KI67 around the CV and PV area; B: Quantification of the KI67 positive cells (<i>n</i> = 6). Data are presented as mean ± SD. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> the CV area of the PCN group , figureFileSmall=/DN4v1gcW3Ix/MlelD4VsA==, figureFileBig=kg4f2HBohRvGzO0/b8K5/Q==, tableContent=null), ArticleFig(id=1208491443962884223, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=33ZOKspJQZBZRqNDJaIJHA==, figureFileBig=RufFd1xua6rCWyUdmZHGZA==, tableContent=null), ArticleFig(id=1208491444122267785, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Figure 5, caption= Dynamic change of PXR downstream genes and triglyceride (TG) after PCN treatment. A: Western blot analysis of PXR downstream metabolizing enzymes of the vehicle and the PCN groups; B: Quantification of proteins mentioned above (<i>n</i> = 3). The yellow dashed line represents the average expression level in the vehicle groups; C: The hepatic TG content of the vehicle and the PCN group at different time point. Data are presented as mean ± SD. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> the vehicle group. P-gp: P-glycoprotein; OATP2: Organic anion transporting polypeptide 2; CYP3A11: Cytochrome P450 3A11; CYP2B10: Cytochrome P450 2B10 , figureFileSmall=33ZOKspJQZBZRqNDJaIJHA==, figureFileBig=RufFd1xua6rCWyUdmZHGZA==, tableContent=null), ArticleFig(id=1208491444252291220, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=cQnsDE2BYSNpLcBuR67sJA==, figureFileBig=/xdNu+hzfvzubUVBJ+imyA==, tableContent=null), ArticleFig(id=1208491444390703263, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Figure 6, caption= Dynamic changes of proliferation-related protein and cyclin-dependent kinases inhibitor protein after PCN treatment. A: Western blot analysis of proliferation-related protein and cyclin-dependent kinases inhibitor protein of the vehicle and the PCN groups; B: Quantification of proteins mentioned above (<i>n</i> = 3). The yellow dashed line represents the average expression level in the vehicle groups. Data are presented as mean ± SD. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> the vehicle group , figureFileSmall=cQnsDE2BYSNpLcBuR67sJA==, figureFileBig=/xdNu+hzfvzubUVBJ+imyA==, tableContent=null), ArticleFig(id=1208491444482977961, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Gene Species Primer sequence
Tnfα Mouse Forward 5'-CAGGCGGTGCCTATGTCTC-3'
Reverse 5'-CGATCACCCCGAAGTTCAGTAG-3'
Ifnγ Mouse Forward 5'-ATGAACGCTACACACTGCATC-3'
Reverse 5'-CCATCCTTTTGCCAGTTCCTC-3'
Il6 Mouse Forward 5'-TAGTCCTTCCTACCCCAATTTCC-3'
Reverse 5'-TTGGTCCTTAGCCACTCCTTC-3'
Gapdh Mouse Forward 5'-AGGTCGGTGTGAACGGATTTG-3'
Reverse 5'-GGGGTCGTTGATGGCAACA-3'
), ArticleFig(id=1208491444617195699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491435180012120, language=CN, label=Table 1, caption=

Primer sequence of pro-inflammatory cytokines genes. Tnfα: Tumor necrosis factor alpha; Ifnγ: Interferon gamma; Il6: Interleukin 6; Gapdh: Glyceraldehyde 3 phosphate dehydrogenase

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene Species Primer sequence
Tnfα Mouse Forward 5'-CAGGCGGTGCCTATGTCTC-3'
Reverse 5'-CGATCACCCCGAAGTTCAGTAG-3'
Ifnγ Mouse Forward 5'-ATGAACGCTACACACTGCATC-3'
Reverse 5'-CCATCCTTTTGCCAGTTCCTC-3'
Il6 Mouse Forward 5'-TAGTCCTTCCTACCCCAATTTCC-3'
Reverse 5'-TTGGTCCTTAGCCACTCCTTC-3'
Gapdh Mouse Forward 5'-AGGTCGGTGTGAACGGATTTG-3'
Reverse 5'-GGGGTCGTTGATGGCAACA-3'
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PXR所致小鼠肝增大的肝细胞动态变化研究
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田佳宁 , 王锐敏 , 杨潇 , 杨洁 , 张翼飞 , 黄民 , 毕惠嫦 *
药学学报 | 研究论文 2021,56(5): 1360-1368
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药学学报 | 研究论文 2021, 56(5): 1360-1368
PXR所致小鼠肝增大的肝细胞动态变化研究
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田佳宁, 王锐敏, 杨潇, 杨洁, 张翼飞, 黄民, 毕惠嫦*
作者信息
  • 中山大学药学院, 药物代谢与药动学实验室, 广东 广州 510006

通讯作者:

*毕惠嫦, Tel: 86-20-39943470, Fax: 86-20-39943000, E-mail:
Dynamic change of hepatocyte during PXR-induced liver enlargement
Jia-ning TIAN, Rui-min WANG, Xiao YANG, Jie YANG, Yi-fei ZHANG, Min HUANG, Hui-chang BI*
Affiliations
  • Lab of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
出版时间: 2021-05-12 doi: 10.16438/j.0513-4870.2021-0493
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摘要
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孕烷X受体（pregnane X receptor，PXR）是核受体超家族成员，在内外源物质代谢、内分泌平衡和细胞增殖等过程中发挥重要调控作用。本课题组前期研究表明，给予PXR鼠源激动剂孕烯醇酮16α-腈（pregnenolone 16α-carbonitrile，PCN）可致小鼠肝增大，并发现此过程肝细胞的变化具有区域性分布的特征：中央静脉（central vein，CV）区肝细胞增大，而门静脉（portal vein，PV）区肝细胞增殖。本研究旨在评估PXR所致肝增大过程肝细胞动态变化的特点。雄性C57BL/6小鼠给予PCN后1、2、3、5天后采集血清及肝脏样本进行生化和病理检测，此动物实验经由中山大学动物伦理委员会批准。结果表明，随着给药时间的延长，小鼠CV区肝细胞体积逐渐增大，PV区肝细胞增殖增加；同时肝细胞增大相关因素如PXR下游细胞色素P450（cytochrome P450，CYP450）代谢酶和转运体的表达以及肝脏甘油三酯（triglyceride，TG）含量均逐渐增加，而肝细胞增殖的增殖相关蛋白的上调以及细胞周期抑制蛋白的下调则在给药初期即有显著变化，提示在PXR所致小鼠肝增大过程中肝细胞增殖的发生早于肝细胞增大。本研究阐明了PXR所致肝增大过程中肝细胞增大与增殖的动态变化，为PXR促进肝增大的研究提供新数据和新观点。

孕烷X受体  /  肝增大  /  肝细胞增大  /  肝细胞增殖

Pregnane X receptor (PXR), a member of nuclear receptor superfamily, plays an important role in xenobiotic and endogenous metabolism, endocrine balance, and cell proliferation, etc. Previous study has shown that pregnenolone 16α-carbonitrile (PCN), a mouse PXR agonist, could induce liver enlargement. And we found that the change in hepatocytes exhibits regional distribution characteristics: hepatocyte enlargement occurs around the central vein (CV) area, while hepatocyte proliferation occurs around the portal vein (PV) area. In this study, the dynamic changes of hepatocytes during PXR-induced liver enlargement were determined. Serum and liver samples from male C57BL/6 mice were collected for biochemical and pathological analysis after PCN treatment for 1, 2, 3, 5 days, respectively. The animal experiment was approved by the Animal Ethics Committee of Sun Yat-Sen University. The results showed that with the increase in the PCN treatment days, the feature of this regional change of hepatocyte around the CV and PV areas became more and more obvious. At the same time, the factors related to hepatocyte enlargement, such as the expression of PXR downstream genes and the hepatic content of triglyceride (TG), has gradually increased. The upregulation of proliferation-related proteins and downregulation of cyclin-dependent kinases inhibitor proteins were observed in the early stage of PCN treatment, suggesting that hepatocyte proliferation occurs earlier than hepatocyte enlargement during PXR-induced liver enlargement. This study reveals the dynamic change of hepatocytes during PXR-induced liver enlargement and provides a new insight in liver enlargement promoted via PXR activation.

pregnane X receptor  /  liver enlargement  /  hepatocyte enlargement  /  hepatocyte proliferation
田佳宁, 王锐敏, 杨潇, 杨洁, 张翼飞, 黄民, 毕惠嫦. PXR所致小鼠肝增大的肝细胞动态变化研究. 药学学报, 2021 , 56 (5) : 1360 -1368 . DOI: 10.16438/j.0513-4870.2021-0493
Jia-ning TIAN, Rui-min WANG, Xiao YANG, Jie YANG, Yi-fei ZHANG, Min HUANG, Hui-chang BI. Dynamic change of hepatocyte during PXR-induced liver enlargement[J]. Acta Pharmaceutica Sinica, 2021 , 56 (5) : 1360 -1368 . DOI: 10.16438/j.0513-4870.2021-0493
正文
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肝脏是机体重要的代谢器官, 负责多种生理过程。在机体代谢改变或疾病等外界环境刺激下, 肝脏能够迅速调整自身大小以维持肝脏功能[1, 2]。如某些疾病的影响导致机体结构和功能发生变化, 肝脏体积会变小[3]。而许多促进肝脏生长和功能需求的刺激, 如激素影响、外源物诱导和细菌感染等则会使肝脏重量增加[4]。肝增大(liver enlargement) 又称作肝肥大(liver hypertrophy)、肝肿大(hepatomegaly) 或肝增生(liver hyperplasia), 包括肝细胞平均大小的增加(hepatocyte enlargement) 以及肝细胞的增殖增加(hyperplasia)[5]。
肝脏基本的结构单位是肝小叶, 肝小叶大致呈六边形, 其中心是中央静脉, 称为中央静脉区(central vein area, CV area, 也称作perivenous/pericentral/centrilobular zone); 六边形的每个角均为门静脉、胆管以及肝动脉组成, 称为门静脉区(portal vein area, PV area, 也称作periportal zone)[6]。肝脏的结构虽然是均匀构成的, 但在功能上却具异质性。目前认为, 肝脏的CV区主要负责外源物的代谢、糖酵解以及脂质胆汁酸等内源物质的合成, PV区主要负责氧气运输、糖异生、脂肪氧化和尿素生成等[7]。
孕烷X受体(pregnane X receptor, PXR) 是核受体超家族成员之一, 主要表达于肝脏中, 在机体内外源物质代谢中发挥重要作用[8]。PXR能够诱导外源物氧化(Ⅰ期)、结合(Ⅱ期) 以及转运(Ⅲ期) 相关基因的表达, 从而调控糖、脂和药物等内外源物质的代谢。1972年首次报道PXR鼠源激动剂孕烯醇酮16α-腈(pregnenolone 16α-carbonitrile, PCN) 能够增加大鼠肝脏重量, 诱导药物代谢酶的活性和滑面内质网的增殖[9]。最初认为PXR促进肝增大是由于水潴留导致肝细胞大小增加[10], 但最近的研究表明, PXR能够增加增殖细胞核抗原(proliferating cell nuclear antigen, PCNA) 阳性细胞数, 说明PXR亦可以促进肝细胞增殖[11]。同时, PXR还可以通过与叉头盒蛋白O (forkhead box protein O, FOXOs) 相互作用抑制其下游细胞周期抑制蛋白, 促进肝细胞增殖[12]。本课题组前期的研究也证明, 鼠源和人源PXR激动剂激活PXR后均显著促进小鼠肝增大, 并发现PXR是通过作用于yes相关蛋白(yes-associated protein, YAP) 信号通路从而促进肝细胞增大或增殖, 该作用是YAP依赖性的[13]。有趣的是, 作者还发现PXR所致肝细胞增殖与增大呈显著的区域性分布: 肝细胞增大主要发生在肝小叶的CV区, 而肝细胞增殖则主要发生在PV区。但是这种区域性分布的动态变化规律尚不清楚。
因此, 本研究旨在阐明PXR所致肝增大过程中, 影响肝细胞增大/增殖的相关因子的动态变化, 为PXR促进肝增大的基础研究提供科学数据。
材料与方法
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药品和试剂  PCN, 纯度= 98% (美国APExBIO公司); 玉米油, 药用级(上海阿拉丁公司); 通用型组织固定液和苏木素-伊红(H&E) 染液(武汉塞维尔生物科技公司); BCA法蛋白定量试剂盒和预染蛋白marker (美国Thermo Fisher Scientific公司); Trizol细胞裂解液(日本Takara公司); 去除基因组DNA试剂盒和预混型qPCR试剂盒(湖南艾科瑞生物工程有限公司); RIPA裂解液(上海博彩生物科技有限公司); loading buffer (杭州弗德生物科技有限公司); 通用型抗体稀释液(苏州新赛美生物科技有限公司); Immobilon Western化学发光HRP底物(美国Merck Millipore公司); 甘油三酯(triglyceride, TG) 试剂盒(南京建成生物工程研究所); anti-β-catenin (CTNNB1) (美国BD公司); anti-KI67 (美国Abcam公司); anti-cytochrome P450 2B10 (CYP2B10)、anti-cytochrome P450 3A11 (CYP3A11) 和anti-cyclin-dependent kinase inhibitor 1B (CDKN1B) (武汉艾博泰克生物科技有限公司); anti-P-glycoprotein (P-gp)、anti-FOXO1和anti-cyclin-dependent kinase inhibitor 1A (CDKN1A) (美国Santa Cruz公司); anti-organic anion transporting polypeptide 2 (OATP2) (美国Affinity Biosciences公司); anti-β-actin、anti-cyclin D1 (CCND1)、anti-proliferating cell nuclear antigen (PCNA)、anti-rabbit IgG-HRP和anti-mouse IgG HRP (美国Cell Signaling Technology公司); anti-retinoblastoma-like protein 2 (RBL2) (上海生工生物工程股份有限公司)。
仪器  AE260电子天平(美国Mettler Toledo公司); URIT-8021A全自动生化分析仪(桂林优利特医疗电子公司); 5417R低温高速离心机、微量移液器和普通PCR仪(德国Eppendorf公司); CX43正置显微镜(日本Olympus株式会社); Precellys 24组织匀浆器(法国Bertin Technologies公司); 全波长读数仪和Nanodrop超微量紫外分光光度计(美国Thermo Fisher Scientific公司); 电泳系统和电转系统(美国Bio-Rad Laboratories公司); ImageQuant LAS 4000显像仪(美国General Electric公司)。
实验动物  C57BL/6雄性小鼠, SPF级, 购买于江苏集萃药康生物科技有限公司, 6周龄, 动物生产许可证号: SCXK (苏) 2018-0008, 实验单位使用许可证号: SYXK (粤) 2016-0112。饲养于中山大学(实验动物中心东校区), 饲养条件: 湿度条件55%~60%, 温度条件22~24 ℃, 室内模拟昼夜交替各12 h, 换气次数维持在每小时10~20次, 小鼠自由摄取水和SPF级小鼠饲料。动物实验经由中山大学伦理委员会批准, 批准号是东-C2020-0302XS。
动物分组与给药  精密称取PCN 200 mg, 加入20 mL玉米油, 充分涡旋混合后超声30 min使其充分溶解, 制备成10 mg·mL-1 PCN溶液, 每次使用前均涡旋并超声处理。
小鼠随机分成8组, 每组6只, 分别命名为1 d-对照组、1 d-PCN组、2 d-对照组、2 d-PCN组、3 d-对照组、3 d-PCN组、5 d-对照组和5 d-PCN组。PCN组每天腹腔注射PCN溶液, 剂量为100 mg·kg-1·d-1, 对照组每天腹腔注射玉米油溶液, 每次注射前均称量小鼠体重, 按照0.01 mL·g-1的标准注射对应体积的溶液。按组别命名连续给药相应天数, 在最后一次给药24 h后, 摘除眼球取血于1.5 mL离心管中, 然后脱臼处死小鼠, 分离肝脏, 称重并拍照。
血清生化指标检测  小鼠血液收集到1.5 mL离心管后, 室温静置30 min, 以3 000 ×g的速度在4 ℃条件下离心15 min, 吸取上清200 μL至1.5 mL离心管中, 送样至广东省医学实验动物中心生化检测室, 检测小鼠血清谷丙转氨酶(alanine transaminase, ALT)、天冬氨酸转氨酶(aspartate transaminase, AST) 和碱性磷酸酶(alkaline phosphatase, ALP) 水平。
组织病理学检测  肝脏组织在通用型组织固定液中固定24 h以上, 送样至武汉塞维尔生物科技公司进行石蜡切片的制备。切片进行脱蜡、抗原修复、伊红-苏木素染色、封片步骤后, 于CX43正置显微镜下观察。
CTNNB1和KI67免疫组化染色  对石蜡切片依次进行脱蜡、抗原修复、淬灭、封闭、孵育抗体、显色、苏木素复染及封片, 最终晾干切片后在CX43正置显微镜下观察。
实时荧光定量PCR检测  按照前期建立方法提取肝脏样本总RNA[14], 根据逆转录及PCR试剂盒说明分别进行RNA逆转录及RT-qPCR反应。所使用引物序列见表 1。
TG含量检测  根据试剂盒说明, 利用GPO-PAP法检测肝脏中总TG含量。
Western blot检测  按照前期所述方法[13], 提取肝脏总蛋白后使用BCA蛋白定量试剂盒调整蛋白浓度至同一水平, 100 ℃加热15 min使蛋白变性, 经过SDS-PAGE电泳和电转、5%脱脂牛奶封闭、孵育一抗及二抗, 最后通过ImageQuant LAS4000系统曝光显影。
数据统计  本研究中的数据均用平均值±标准差(mean ± SD) 表示。首先使用Image J软件对免疫组化及蛋白表达结果进行量化, 然后使用GraphPad Prism 8.3.0软件对定量后的数据进行统计学分析并制作图表, 采用Unpaired Student's t-test检验(two-tailed) 比较两组间的差异, 当P < 0.05时认为两组数据之间的差异具有统计学意义。
结果
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1 PCN促进小鼠肝增大
在不同天数给予雄性C57BL/6小鼠PCN或玉米油, 如图 1A所示, 给予PCN后小鼠肝脏明显增大, 并且随着给药天数的增加, 肝脏大小逐渐增加。与对照组相比, 给予PCN 1天后, 小鼠的肝重比由5.11%上升至5.94%, 给予PCN 5天后, 肝重比增加至6.93% (图 1B)。
2 PXR所致小鼠肝增大为生理性肝增大
本研究进一步检测了小鼠血清中ALT、AST和ALP水平以及促炎细胞因子表达水平, 以判断PXR所致肝增大是否有肝损伤。H&E染色结果显示并未出现炎症细胞浸润的明显特征(图 2A), 说明肝脏不存在损伤性病理变化。血清中ALT、AST和ALP的含量变化可以反映肝脏急性损伤程度。如图 2B所示, 在给予小鼠PCN后, 血清AST和ALP水平与对照组无明显升高, 给予PCN 5天后小鼠血清ALT水平上升至41.2 U·L-1, 但仍在小鼠ALT正常参考值水平内(49.53 ± 11.05) U·L-1 [15]; 同时, 促炎细胞因子Tnfα、Ifnγ和Il6的表达与对照组相比同样没有显著性变化(图 2C)。以上结果表明, PCN促进小鼠肝增大过程中并未出现急性肝损伤, PXR激动后所致肝增大表现为生理性肝增大。
3 PXR所致CV区肝细胞增大的动态变化
CTNNB1主要表达于细胞膜上, 本研究通过对CTNNB1进行免疫组化染色以勾勒肝细胞的形态, 并由此观察肝细胞体积的变化。如图 3A所示, 给予PCN 1天后, 肝脏CV区的肝细胞与对照组相比没有明显变化(438.7 ± 31.7)μm2, 但给予PCN 2天后, 肝细胞大小增加到(477.3 ± 21.1) μm2, 并在5天后达到(552.4 ± 15.0) μm2; 而PV区的肝细胞虽有轻微的变大趋势, 但在给予PCN 5天后, 肝细胞大小[(431.4 ± 15.8) μm2] 与对照组相比仍无显著性差异(图 3B)。同时, PCN致CV区肝细胞增大的幅度随给药时间的延长不断增加, 并且在第5天增加了19.9% (图 3C)。
4 PXR所致PV区肝细胞增殖的动态变化
KI67是一种与细胞增殖密切相关的蛋白, 它在细胞分裂各期均能被检测到, 而在静息期(G0期) 无表达。利用KI67免疫组化染色判断肝细胞的增殖情况。图 4A表明给予PCN 1天后, 肝细胞即出现增殖, 且主要集中在PV区, KI67阳性细胞比例为3.32% (图 4B), CV区肝细胞也出现少量增殖, KI67阳性细胞比例为0.95%; 给予PCN 5天后, 这种区域分布的现象更加明显, PV区KI67阳性细胞比例为2.54%, 而CV区KI67阳性细胞仅为0.13%。
5 PXR下游靶蛋白表达及TG水平的动态变化
根据以上结果, 作者推测PXR诱导肝脏CV区肝细胞增大可能是由于具有中央静脉偏倚的PXR下游代谢酶/转运体表达增加和/或糖脂等物质积聚所致, 因此, 本研究检测了PXR下游代谢酶/转运体以及TG的动态变化。如图 5A所示, PXR激动后, 下游Ⅰ相代谢酶CYP2B10 (人CYP2B6) 和CYP3A11 (人CYP3A4) 以及转运体P-gp和OATP2的表达均随着给药时间的延长而不断上调。其中, CYP3A11和CYP2B10在5天分别上调了3.7倍和2.6倍, 而P-gp和OATP2则在3天表达达到峰值, 分别上调了1.7倍和1.6倍(图 5B); TG合成从给予PCN 1天时开始增加, 并在5天达到最大(0.010 3 mmol·g-1组织) (图 5C)。以上结果说明, PXR可以使诱导代谢酶及转运体的表达逐渐增加, 同时使TG合成增加。
6 细胞增殖相关蛋白和细胞周期抑制蛋白的动态变化
本研究进一步检测了与肝细胞增殖相关的细胞增殖相关蛋白和细胞周期抑制蛋白的动态变化。如图 6所示, 给予PCN 1天后, 细胞增殖相关蛋白PCNA和CCND1立刻上调, 分别上调了2.2倍和1.48倍; 而CDKN1B、CDKN1A和RBL2等细胞周期抑制因子的表达显著下调(图 6A), 说明给予PCN后肝细胞出现显著增殖。有趣的是, CDKN1A在给予PCN 1天后的表达水平最低, 下调了49%, 而RBL2和CDKN1B则是在第5天表达最低, 分别下调了47%和59% (图 6B)。以上结果说明, PCN激动PXR后通过上调细胞增殖相关蛋白、下调细胞周期抑制因子, 从而显著促进肝细胞增殖。
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肝脏是机体重要的代谢器官, 负责多种生理过程。肝脏能够根据外界环境的改变或机体生理病理状态迅速调节自身大小, 从而维持肝脏功能的稳态[16]。本课题组前期研究发现, 给予小鼠PXR激动剂PCN (100 mg·kg-1·d-1) 5天可导致显著肝增大, 并伴随有肝细胞增大与肝细胞增殖出现[13]。导致肝增大的原因众多, 根据是否伴随肝损伤的发生, 肝增大可以分为良性与病理性两类。在本研究中, 反映肝脏急性损伤的指标血清AST和ALP均无显著变化, 血清ALT水平在给予PCN 5天后上升了约1.6倍, 而ALT水平至少上升2倍才提示肝脏发生损伤[5]。据报道, C57BL/6雄性小鼠血清ALT水平正常参考值为(49.53 ± 11.05) U·L-1[15], 本研究中血清ALT水平均处于正常值范围内, 说明给予PCN 5天后的ALT水平升高可能是由于活动和饮食而造成的[17]。同时, 促炎细胞因子Tnfα、Ifnγ和Il6的表达同样没有明显变化, H&E染色亦未发现明显的病理损伤。这些结果表明, PXR所致小鼠肝增大是生理性(良性) 肝增大。
肝增大从组织学上表现为肝细胞增大以及肝细胞增殖, 本研究发现, 在给予PCN后, 小鼠肝脏CV区的肝细胞表现为体积增大, 并且随着给药时间的延长, 肝细胞大小也在不断增加; 而PV区肝细胞的大小没有增大, 主要以增殖为主。研究表明, 肝脏重量至少增加20%才能够在组织学上观察到肝细胞增大[5]。本研究中, 给予PCN 5天使小鼠肝脏增重近30%, 对比肝细胞增大和增殖的程度可以发现, CV区肝细胞尺寸增加近20%, 而KI67+肝细胞占比仅在4%左右, 这表明肝细胞增殖对于肝脏重量的贡献度可能不占主导地位。据报道, 肝细胞增大的分布位置与酶诱导剂的剂量有密切关系, 高剂量可能会导致中心区域甚至整个小叶出现肝细胞增大的现象, 这可能与代谢酶分布、血流等差异有关。从结果中可以看出, KI67+肝细胞分布在紧邻PV区附近(图 3A), 而PV区肝细胞的大小呈现上升的趋势(图 2C), 说明肝细胞增大的范围比较弥散。据此推测, CV区肝细胞增大可能对PXR所致肝增大贡献更大, 但后续还需要更直观的实验进一步证明, 例如检测肝脏DNA含量的变化等。
研究表明, 肝细胞增大也可能是由于水、糖原和脂质等物质的累积或是亚细胞器的增殖所导致的, 酶诱导导致的肝细胞增大体现在蛋白质合成增加或细胞器数目增加[4]。过氧化物酶体增殖物激活受体α (peroxisome proliferator activated receptor α, PPARα) 激动引起的肝细胞增大是由过氧化物酶体和内质网的增殖造成的, 并伴随着CYP4A的特异性表达上调[18]; 组成型雄甾烷受体(constitutive androstane receptor, CAR) 激动剂苯巴比妥诱导的肝细胞增大同样发生在CV区, 并且诱导内质网显著增殖[19], 这提示核受体激活导致的肝细胞增大可能与内质网增殖相关。同时, PXR可以促进脂质合成以及代谢酶的表达, 而大多数CYP450均表达于CV区附近[20], 因此肝细胞增大可能由于PXR诱导CYP450表达增加和内质网的增殖所致。本研究中, 给予PCN后, PXR下游代谢酶CYP3A11、CYP2B10的表达随着给药天数的增加而不断增加, 并在5天时达到峰值, 而转运体P-gp和OATP2则在3天达到峰值。同样地, TG的合成也随着给药天数增加而增加, 以上结果与CV区肝细胞增大的动态变化规律相吻合。
肝细胞从静息期转换至增殖期需要细胞周期蛋白依赖性激酶(cyclin-dependent kinases, CDKs) 的参与[21]。CDKs本身无活性, 需要与一个正调节亚基结合组成二元复合物才能发挥作用, 这个正调节亚基即细胞周期蛋白(cyclins), 其中CCND1与CDK4/6结合共同调控细胞的G1进程[22]。此外, CDKs的激活作用还受到CDK抑制因子(CDK inhibitors, CKIs) 的负调控作用, CKIs的失活或下调能促进细胞增殖[23, 24]。FOXOs家族在细胞增殖、凋亡和炎症等多个方面均有重要的调控作用, 其中, FOXOs对细胞周期进程的影响主要体现在对CKIs的表达调控, FOXO的激活可以导致多种CKIs的表达上调从而阻滞细胞周期[25]。有研究者发现, PXR通过与FOXOs相互作用, 从而抑制CKIs的表达, 最终促进肝细胞增殖[12]。本研究中, FOXO1及其下游细胞周期抑制蛋白RBL2、CDKN1A、CDKN1B的表达在给予PCN后立刻被抑制, 与前述PXR促进肝细胞增殖结果一致。
值得注意的是, 在给予PCN 1天后, CV区肝细胞没有显著性增大, 而PV区肝细胞则已开始增殖。而且CCND1在前期的表达高于后期, 同时, 细胞周期S期的增殖蛋白标志物PCNA也具有同样的表达趋势, 这提示在PXR致小鼠肝增大过程中可能存在肝细胞变化的先后性, 即PV区肝细胞增殖早于CV区肝细胞增大出现, 这与前述肝细胞动态变化结果相一致。
本研究表明激动PXR能够促进小鼠生理性肝增大, 本课题组前期研究还发现护肝中药五味子中主要活性成分五味子醇乙能够通过激动PXR促进良性肝增大[26], 通过激动PXR抵抗胆汁淤积性肝损伤[27], 通过激动PXR促进部分肝切除后肝再生与修复[28]。这些研究结果提示, PXR具有促进肝损伤后再生和修复的重要作用。通常情况下, 肝脏增大与肝细胞癌的发生发展有密切关系。在一项为期两年的慢性致癌研究中, 认定肝细胞增大和肝细胞坏死是预测肝癌发生的最佳指标[29], 但有研究表明, 长期激动PXR不仅不会导致肝癌的发生, 还能够通过抑制肝癌细胞的上皮-间质转化减缓核受体CAR介导的肝癌的发生发展[30]。本研究中PXR所致肝增大能够上调CYP450及转运体从而增强肝脏外源物代谢功能, 同时近年的研究还指出PXR在调节类固醇激素稳态、肝脏脂肪变性和炎症性肠病等发挥重要防治作用[31]。因此, PXR有望成为抵抗肝脏疾病的极具潜力和前景的靶点。
综上所述, 本研究证明PXR所致小鼠生理性肝增大表现为CV区肝细胞增大以及PV区肝细胞增殖, 并阐明了在PXR所致小鼠肝增大过程中肝细胞增大与肝细胞增殖的动态变化以及肝细胞增大/增殖相关因素的动态变化特征, 为PXR促进肝增大的基础研究提供了新数据和新观点。
作者贡献: 田佳宁负责实验部分设计、实验实施、结果分析与统计、撰写论文; 王锐敏、杨洁和张翼飞负责部分实验的实施; 杨潇负责部分实验的设计与指导; 黄民和毕惠嫦负责研究思路的提出、实验设计以及修订论文。
利益冲突: 本文所有作者之间不存在利益冲突。
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  • 国家自然科学基金资助项目(81973392)
  • 国家自然科学基金资助项目(82025034)
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doi: 10.16438/j.0513-4870.2021-0493
  • 接收时间：2021-04-05
  • 首发时间：2025-12-18
  • 出版时间：2021-05-12
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  • 收稿日期：2021-04-05
  • 修回日期：2021-04-15
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国家自然科学基金资助项目(81973392)
国家自然科学基金资助项目(82025034)
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    中山大学药学院, 药物代谢与药动学实验室, 广东 广州 510006

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