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Article(id=1201096920207942191, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-1158, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1696953600000, receivedDateStr=2023-10-11, revisedDate=1699891200000, revisedDateStr=2023-11-14, acceptedDate=null, acceptedDateStr=null, onlineDate=1764293421079, onlineDateStr=2025-11-28, pubDate=1712851200000, pubDateStr=2024-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764293421079, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764293421079, creator=13701087609, updateTime=1764293421079, updator=13701087609, issue=Issue{id=1201096916940579367, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='4', pageStart='789', pageEnd='1100', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764293420298, creator=13701087609, updateTime=1764293534792, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201097397242912862, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201097397242912863, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=939, endPage=947, ext={EN=ArticleExt(id=1201096921243935294, articleId=1201096920207942191, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The improvement provided by physcion on non-alcoholic fatty liver disease in mice, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Physcion (PHY) is an anthraquinone compound derived from traditional Chinese medicine such as Rhei Radix et Rhizoma. The aim of this study is to investigate the improvement of PHY on non-alcoholic fatty liver disease (NAFLD) and its underlying mechanism. NAFLD was induced in mice by feeding with the methionine- and choline-deficient diet (MCD) for 6 weeks. This experiment was approved by the Experimental Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (approval number: PZSHUTCM190705019). The results displayed that PHY (5 and 20 mg·kg-1) reversed liver damage, reduced hepatic lipid accumulation and decreased the elevated NAFLD activity score (NAS) in MCD-fed NAFLD mice. Results from Western blot and enzyme activity demonstrated that PHY could enhance the protein expression and enzyme activity of carnitine palmitoyltransferase 1A (CPT1A) in the liver and L-02 cells, but it did not affect Cpt1a mRNA expression. Immunofluorescence results indicated that PHY (10 and 25 μmol·L-1) could reduce the mitochondrial injury induced by non-esterified fatty acids (NEFA) in L-02 cells. Results from seahorse assay showed that PHY could enhance mitochondrial basic respiration, maximal respiration, ATP synthesis and reserve respiration in L-02 cells treated with NEFA, but had no effect on mitochondrial proton leakage. In summary, PHY reversed mitochondrial damage and enhanced fatty acid β-oxidation, thereby reducing hepatic steatosis and improving NAFLD.

, correspAuthors=Hao OUYANG, Li-li JI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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=Jin-yu ZHANG, Shao-bo ZHANG, Hong XU, Hao OUYANG, Li-li JI), CN=ArticleExt(id=1201096924112839336, articleId=1201096920207942191, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=大黄素甲醚改善小鼠非酒精性脂肪性肝病的研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

大黄素甲醚(physcion, PHY) 是一种来源于大黄等中药的蒽醌类化合物。本实验旨在探究PHY对非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD) 的改善作用及其机制。采用蛋氨酸胆碱缺乏饲料(methionine- and choline-deficient diet, MCD) 喂养6周诱导小鼠NAFLD疾病模型(本实验获得上海中医药大学实验动物伦理委员会批准, 批准号: PZSHUTCM190705019)。结果显示, PHY (5和20 mg·kg-1) 能改善MCD诱导NAFLD小鼠的肝损伤, 减轻肝脏脂肪累积, 降低升高的NAFLD活动性评分(NAFLD activity score, NAS)。Western blot及酶活力实验结果提示, PHY能提升肝脏及L-02细胞中肉毒碱棕榈酰基转移酶1A (carnitine palmitoyltransferase 1A, CPT1A) 蛋白表达及酶活力, 但real-time PCR结果显示PHY不影响Cpt1a mRNA表达。免疫荧光结果提示, PHY (10和25 μmol·L-1) 能缓解游离脂肪酸(non-esterified fatty acids, NEFA) 诱导的人正常肝L-02细胞中的线粒体损伤。Seahorse实验结果提示, PHY给药后能提升L-02细胞内线粒体基础呼吸能力、最大呼吸能力、ATP合成和储备呼吸能力, 但不影响线粒体质子漏。以上研究表明, PHY可能通过改善线粒体功能, 促进脂肪酸β氧化, 减少肝脏中脂肪的堆积, 发挥改善NAFLD的药效。

, correspAuthors=欧阳豪, 季莉莉, authorNote=null, correspAuthorsNote=
*季莉莉, Tel: 86-21-51322517, E-mail: ;
欧阳豪, E-mail:
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2. Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1201096927216624464, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, authorId=1201096925845087021, language=CN, stringName=欧阳豪, firstName=豪, middleName=null, lastName=欧阳, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, *, address=1.上海中医药大学中药研究所, 中药标准化教育部重点实验室, 中药新资源与质量标准综合评价国家中医药管理局重点研究室, 上海市复方中药重点实验室, 上海 201203
2.上海中医药大学附属岳阳中西医结合医院肝病科, 上海 201203, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1201096924351914682, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, xref=null, ext=[AuthorCompanyExt(id=1201096924360303291, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, companyId=1201096924351914682, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China), AuthorCompanyExt(id=1201096924486132424, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, companyId=1201096924473549509, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.上海中医药大学附属岳阳中西医结合医院肝病科, 上海 201203)])], figs=[ArticleFig(id=1201096929271832577, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=TdyaXrprtYqPmL6GRb5hFQ==, figureFileBig=hVGpTf1JYsAVvDWeFyCKMA==, tableContent=null), ArticleFig(id=1201096929385078795, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Figure 1, caption= The effect of PHY on liver injury in MCD-induced NAFLD mice. A: H & E staining and Sirius red staining of liver tissue (200×); B: NAFLD activity score; C: Serum AST activity; D: Serum ALT activity. <i>n</i> = 6-7, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± SEM. <sup>***</sup><i>P</i> < 0.001 <i>vs</i> MCS group; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> MCD group. MCS: Methionine- and choline-supplement diet; MCD: Methionine- and choline-deficient diet; PGZ: Pioglitazone; PHY: Physcion; NAFLD: Non-alcoholic fatty liver disease; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; H & E: Hematoxylin-eosin staining , figureFileSmall=TdyaXrprtYqPmL6GRb5hFQ==, figureFileBig=hVGpTf1JYsAVvDWeFyCKMA==, tableContent=null), ArticleFig(id=1201096929716428851, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=9qMp8NCyAfGzLCyz6NI+wQ==, figureFileBig=nvKMdn5UUB75fQvCTgkqGg==, tableContent=null), ArticleFig(id=1201096929930338362, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Figure 2, caption= The effect of PHY on lipid accumulation in MCD-induced NAFLD mice. A: Oil red O staining (ORO, 200×); B: Liver TG content; C: Liver NEFA content. <i>n</i> = 6-7, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± SEM. <sup>**</sup><i>P</i> < 0.01 <i>vs</i> MCS group; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> MCD group. TG: Triglyceride; NEFA: Non-esterified fatty acids , figureFileSmall=9qMp8NCyAfGzLCyz6NI+wQ==, figureFileBig=nvKMdn5UUB75fQvCTgkqGg==, tableContent=null), ArticleFig(id=1201096930035195971, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=UNXbYPQaKie6QlSDAjgHqQ==, figureFileBig=KT7fA+dTWpeUsFNn/jgb5w==, tableContent=null), ArticleFig(id=1201096930177802322, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Figure 3, caption= The effect of PHY on hepatic protein expression, enzyme activity of CPT1A and mRNA expression of <i>β</i>-oxidation-associated genes in MCD-induced NAFLD mice. A: Hepatic <i>Cpt1a</i> mRNA expression; B: Hepatic CPT1A protein expression; C: Hepatic CPT1A enzyme activity; D: Hepatic <i>Acads</i>, <i>Acadm</i>, <i>Acadl</i>, and <i>Acadvl</i> mRNA expression. <i>n</i> = 3-5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± SEM. <sup>**</sup><i>P</i> < 0.01 <i>vs</i> MCS group; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> MCD group , figureFileSmall=UNXbYPQaKie6QlSDAjgHqQ==, figureFileBig=KT7fA+dTWpeUsFNn/jgb5w==, tableContent=null), ArticleFig(id=1201096930307825756, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=TU7mbJWxGvoVebXQ2KDgFQ==, figureFileBig=EIyFaWOo6V6QY+DIeLusgw==, tableContent=null), ArticleFig(id=1201096930433654888, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Figure 4, caption= The effect of PHY on CPT1A protein expression and enzyme activity <i>in vitro</i>. A: CPT1A protein expression in L-02 cells; B: Enzyme activity of CPT1A in L-02 cells. <i>n</i> =3-4, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± SEM. <sup>*</sup><i>P</i> < 0.05 <i>vs</i> BSA group; <sup>#</sup><i>P</i> < 0.05 <i>vs</i> NEFA group. BSA: Bovine serum albumin , figureFileSmall=TU7mbJWxGvoVebXQ2KDgFQ==, figureFileBig=EIyFaWOo6V6QY+DIeLusgw==, tableContent=null), ArticleFig(id=1201096930542706803, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=u2fAbLBDwffWsFQInhhWbQ==, figureFileBig=6u36sDZtZ+PwUqqH38TYqQ==, tableContent=null), ArticleFig(id=1201096931633225853, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Figure 5, caption= The effect of PHY on mitochondrial function and mitochondrial quantity. A: Mito-tracker red staining (200×); B: Detection of mitochondrial energy metabolism in L-02 cells; C: Hepatic mtDNA copy numbers; D: Hepatic <i>Nrf1</i>, <i>Ppargc1a</i>, and <i>Tfam</i> mRNA expression. <i>n</i> = 3-5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± SEM. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> BSA group or MCS group; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01 <i>vs</i> NEFA group or MCD group. OCR: Oxygen consumption rate; FCCP: Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; AA: Antimycin A , figureFileSmall=u2fAbLBDwffWsFQInhhWbQ==, figureFileBig=6u36sDZtZ+PwUqqH38TYqQ==, tableContent=null), ArticleFig(id=1201096931763249287, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=XYRsj1Idsji2/K/0dw6wYg==, figureFileBig=KKb6MmQCMgI6ee3hOFLDSw==, tableContent=null), ArticleFig(id=1201096931889078416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Figure 6, caption= The effect of PHY on hepatic lipase enzyme activity in MCD-induced NAFLD mice. A: Expression of lipase enzyme-related gene in liver; B: Hepatic lipase C activity. <i>n</i> = 4-6, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± SEM. <sup>***</sup><i>P</i> < 0.001 <i>vs</i> MCS group; <sup>#</sup><i>P</i> < 0.05, <sup>##</sup><i>P</i> < 0.01 <i>vs</i> MCD group , figureFileSmall=XYRsj1Idsji2/K/0dw6wYg==, figureFileBig=KKb6MmQCMgI6ee3hOFLDSw==, tableContent=null), ArticleFig(id=1201096932044267672, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GenePrimerSequence
Cpt1aForward5'-TATGGTCAAGGTCTTCTCGGGTCG-3'
Reverse5'-AGTGCTGTCATGCGTTGGAAGTCTC-3'
AcadvlForward5'-GATTCCTGTCCTCCGTCTC-3'
Reverse5'-GGCTCTGCAAGGCTGTAT-3'
AcadlForward5'-TTCAGATGCCCAGTATTTT-3'
Reverse5'-GCCTGTGAGTTCATGTTTG-3'
AcadmForward5'-TAACATACTCGTCACCCTTC-3'
Reverse5'-ATGCCTGTGATTCTTGCT-3'
AcadsForward5'-AGGGTTTGCATGGCTATTT-3'
Reverse5'-TATCAGTGCCTTCCTGGTTC-3'
Nrf1Forward5'-AGCACGGAGTGACCCAAAC-3'
Reverse5'-TGTACGTGGCTACATGGACCT-3'
TfamForward5'-ATTCCGAAGTGTTTTTCCAGCA-3'
Reverse5'-TCTGAAAGTTTTGCATCTGGGT-3'
Ppargc1aForward5'-TATGGAGTGACATAGAGTGTGCT-3'
Reverse5'-CCACTTCAATCCACCCAGAAAG-3'
LipaForward5'-TGTTCGTTTTCACCATTGGGA-3'
Reverse5'-CGCATGATTATCTCGGTCACA-3'
LipcForward5'-ATGGGAAATCCCCTCCAAATCT-3'
Reverse5'-GTGCTGAGGTCTGAGACGA-3'
Nd1Forward5'-CTAGCAGAAACAAACCGGGC-3'
Reverse5'-CCGGCTGCGTATTCTACGTT-3'
18SForward5'-CGCGGTTCTATTTTGTTGGT-3'
Reverse5'-AGTCGGCATCGTTTATGGTC-3'
ActbForward5'-TTCGTTGCCGGTCCACACCC-3'
Reverse5'-GCTTTGCACATGCCGGAGCC-3'
), ArticleFig(id=1201096932224622755, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096920207942191, language=CN, label=Table 1, caption=

The primer sequences of mouse gene. Cpt1α: Carnitine palmitoyteansferase 1A; Acadvl: Acyl-coenzyme A (Acyl-CoA) dehydrogenase very long chain; Acadl: Acyl-CoA dehydrogenase, long-chain; Acadm: Acyl-CoA dehydrogenase medium chain; Acads: Acyl-CoA dehydrogenase short chain; Nrf1: Nuclear respiratory factor 1; Tfam: Transcription factor A, mitochondrial; Ppargc1a: Peroxisome proliferative activated receptor gamma coactivator 1 alpha; Lipa: Lipase A; Lipc: Lipase C; Nd1: NADH dehydrogenase subunit 1; 18S: 18S ribosomal RNA; Actb: Actin; Forward: Forward primers; Reverse: Reverse primers

, figureFileSmall=null, figureFileBig=null, tableContent=
GenePrimerSequence
Cpt1aForward5'-TATGGTCAAGGTCTTCTCGGGTCG-3'
Reverse5'-AGTGCTGTCATGCGTTGGAAGTCTC-3'
AcadvlForward5'-GATTCCTGTCCTCCGTCTC-3'
Reverse5'-GGCTCTGCAAGGCTGTAT-3'
AcadlForward5'-TTCAGATGCCCAGTATTTT-3'
Reverse5'-GCCTGTGAGTTCATGTTTG-3'
AcadmForward5'-TAACATACTCGTCACCCTTC-3'
Reverse5'-ATGCCTGTGATTCTTGCT-3'
AcadsForward5'-AGGGTTTGCATGGCTATTT-3'
Reverse5'-TATCAGTGCCTTCCTGGTTC-3'
Nrf1Forward5'-AGCACGGAGTGACCCAAAC-3'
Reverse5'-TGTACGTGGCTACATGGACCT-3'
TfamForward5'-ATTCCGAAGTGTTTTTCCAGCA-3'
Reverse5'-TCTGAAAGTTTTGCATCTGGGT-3'
Ppargc1aForward5'-TATGGAGTGACATAGAGTGTGCT-3'
Reverse5'-CCACTTCAATCCACCCAGAAAG-3'
LipaForward5'-TGTTCGTTTTCACCATTGGGA-3'
Reverse5'-CGCATGATTATCTCGGTCACA-3'
LipcForward5'-ATGGGAAATCCCCTCCAAATCT-3'
Reverse5'-GTGCTGAGGTCTGAGACGA-3'
Nd1Forward5'-CTAGCAGAAACAAACCGGGC-3'
Reverse5'-CCGGCTGCGTATTCTACGTT-3'
18SForward5'-CGCGGTTCTATTTTGTTGGT-3'
Reverse5'-AGTCGGCATCGTTTATGGTC-3'
ActbForward5'-TTCGTTGCCGGTCCACACCC-3'
Reverse5'-GCTTTGCACATGCCGGAGCC-3'
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大黄素甲醚改善小鼠非酒精性脂肪性肝病的研究
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张进宇 1 , 张少波 1 , 徐红 1 , 欧阳豪 1, 2, * , 季莉莉 1, *
药学学报 | 研究论文 2024,59(4): 939-947
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药学学报 | 研究论文 2024, 59(4): 939-947
大黄素甲醚改善小鼠非酒精性脂肪性肝病的研究
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张进宇1, 张少波1, 徐红1, 欧阳豪1, 2, * , 季莉莉1, *
作者信息
  • 1.上海中医药大学中药研究所, 中药标准化教育部重点实验室, 中药新资源与质量标准综合评价国家中医药管理局重点研究室, 上海市复方中药重点实验室, 上海 201203
  • 2.上海中医药大学附属岳阳中西医结合医院肝病科, 上海 201203

通讯作者:

*季莉莉, Tel: 86-21-51322517, E-mail: ;
欧阳豪, E-mail:
The improvement provided by physcion on non-alcoholic fatty liver disease in mice
Jin-yu ZHANG1, Shao-bo ZHANG1, Hong XU1, Hao OUYANG1, 2, * , Li-li JI1, *
Affiliations
  • 1. The MOE Key Laboratory for Standardization of Chinese Medicines, the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
  • 2. Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
出版时间: 2024-04-12 doi: 10.16438/j.0513-4870.2023-1158
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摘要
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大黄素甲醚(physcion, PHY) 是一种来源于大黄等中药的蒽醌类化合物。本实验旨在探究PHY对非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD) 的改善作用及其机制。采用蛋氨酸胆碱缺乏饲料(methionine- and choline-deficient diet, MCD) 喂养6周诱导小鼠NAFLD疾病模型(本实验获得上海中医药大学实验动物伦理委员会批准, 批准号: PZSHUTCM190705019)。结果显示, PHY (5和20 mg·kg-1) 能改善MCD诱导NAFLD小鼠的肝损伤, 减轻肝脏脂肪累积, 降低升高的NAFLD活动性评分(NAFLD activity score, NAS)。Western blot及酶活力实验结果提示, PHY能提升肝脏及L-02细胞中肉毒碱棕榈酰基转移酶1A (carnitine palmitoyltransferase 1A, CPT1A) 蛋白表达及酶活力, 但real-time PCR结果显示PHY不影响Cpt1a mRNA表达。免疫荧光结果提示, PHY (10和25 μmol·L-1) 能缓解游离脂肪酸(non-esterified fatty acids, NEFA) 诱导的人正常肝L-02细胞中的线粒体损伤。Seahorse实验结果提示, PHY给药后能提升L-02细胞内线粒体基础呼吸能力、最大呼吸能力、ATP合成和储备呼吸能力, 但不影响线粒体质子漏。以上研究表明, PHY可能通过改善线粒体功能, 促进脂肪酸β氧化, 减少肝脏中脂肪的堆积, 发挥改善NAFLD的药效。

大黄素甲醚  /  非酒精性脂肪性肝病  /  肉毒碱棕榈酰基转移酶1A  /  β氧化  /  线粒体损伤

Physcion (PHY) is an anthraquinone compound derived from traditional Chinese medicine such as Rhei Radix et Rhizoma. The aim of this study is to investigate the improvement of PHY on non-alcoholic fatty liver disease (NAFLD) and its underlying mechanism. NAFLD was induced in mice by feeding with the methionine- and choline-deficient diet (MCD) for 6 weeks. This experiment was approved by the Experimental Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (approval number: PZSHUTCM190705019). The results displayed that PHY (5 and 20 mg·kg-1) reversed liver damage, reduced hepatic lipid accumulation and decreased the elevated NAFLD activity score (NAS) in MCD-fed NAFLD mice. Results from Western blot and enzyme activity demonstrated that PHY could enhance the protein expression and enzyme activity of carnitine palmitoyltransferase 1A (CPT1A) in the liver and L-02 cells, but it did not affect Cpt1a mRNA expression. Immunofluorescence results indicated that PHY (10 and 25 μmol·L-1) could reduce the mitochondrial injury induced by non-esterified fatty acids (NEFA) in L-02 cells. Results from seahorse assay showed that PHY could enhance mitochondrial basic respiration, maximal respiration, ATP synthesis and reserve respiration in L-02 cells treated with NEFA, but had no effect on mitochondrial proton leakage. In summary, PHY reversed mitochondrial damage and enhanced fatty acid β-oxidation, thereby reducing hepatic steatosis and improving NAFLD.

physcion  /  non-alcoholic fatty liver disease  /  carnitine palmitoyltransferase 1A  /  β-oxidation  /  mitochondrial damage
张进宇, 张少波, 徐红, 欧阳豪, 季莉莉. 大黄素甲醚改善小鼠非酒精性脂肪性肝病的研究. 药学学报, 2024 , 59 (4) : 939 -947 . DOI: 10.16438/j.0513-4870.2023-1158
Jin-yu ZHANG, Shao-bo ZHANG, Hong XU, Hao OUYANG, Li-li JI. The improvement provided by physcion on non-alcoholic fatty liver disease in mice[J]. Acta Pharmaceutica Sinica, 2024 , 59 (4) : 939 -947 . DOI: 10.16438/j.0513-4870.2023-1158
正文
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非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD) 是全球范围内最常见的慢性肝脏疾病之一[1]。NAFLD被定义为在没有饮酒史或其他致病因素的条件下, 肝细胞中脂肪过度累积(> 5%) 为主要特征的临床病理表现[2, 3], 该病在早期阶段具有隐蔽性, 若不加以治疗, 会进一步发展为晚期严重阶段的非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH), 且NASH会进一步恶化发展为终末期肝病甚至肝癌[4, 5]。近年来NAFLD的发病率急剧升高, 预计到2030年中国将成为全世界NAFLD发病率最高的国家, 患病人数高达3.145 8亿[6, 7]。NAFLD发病率的激增给全球尤其是我国的经济和卫生资源带来了巨大压力。现阶段防治NAFLD的手段主要包括减肥、运动、控制饮食等手段, 无FDA批准的药物上市[8, 9]。而这些治疗手段患者依从性差, 因此寻找安全有效的药物对治疗NAFLD有重大意义。
肝脏脂肪累积是NAFLD患者最主要的病理变化, 正常生理状态下肝脏能自我调节脂肪酸代谢, 维持肝脏正常功能, 而当机体摄入过量脂肪后甘油三酯(triglyceride, TG) 在肝脏中沉积引发肝脏脂肪变性[10], 进而导致肝脏能量代谢紊乱[11]。线粒体对维持肝脏正常生理功能具有重要意义[12]。线粒体β氧化是肝细胞分解代谢脂肪酸的最主要途径[13]。肝脏中蓄积的过量脂肪酸导致肝脏线粒体功能受损产生大量活性氧(reactive oxygen species, ROS), 导致电子渗漏增强, 同时引发细胞中其他生物大分子氧化修饰, 加剧肝损伤[14, 15]。位于线粒体外膜上的肉碱棕榈酰转移酶1A (carnitine palmitoyltransferase 1A, CPT1A) 主要负责转运长链脂肪酸进入线粒体, 是线粒体脂肪酸β氧化的关键限速酶[16]。增强CPT1A酶活力能提高线粒体β氧化功能, 减少肝脏脂肪累积[17]。可见, 维持线粒体正常功能、减少肝脏脂肪累积是治疗NAFLD的重要手段。
大黄素甲醚(physcion, PHY) 是一种来源于大黄等中药的蒽醌类化合物, 已有文献[18]报道PHY具有抗炎、抗肿瘤等多种生物活性。但是, 目前尚无研究评价PHY改善NAFLD的药效。本实验将在蛋氨酸胆碱缺乏饲料喂养(methionine- and choline-deficient diet, MCD) 诱导NAFLD小鼠的动物模型上, 探讨PHY对NAFLD的改善作用, 并初步探索其作用机制。
材料与方法
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药物和仪器  PHY (货号: PRF9030521) 购自上海源叶生物科技有限公司; 吡格列酮(pioglitazone, PGZ; 货号: 41-529F) 购自江苏万邦生化医药集团有限责任公司; 蛋氨酸胆碱补充饲料(methionine- and choline-supplement diet, MCS; 货号: TP3005GS)、MCD (货号: TP3005G) 购自南通特洛菲饲料科技有限公司; Trizol (货号: AL11815A) 购自宝日医生物技术有限公司; Evo M-MLV RT Mix Kit with gDNA Clean for qPCR Ver.2 (货号: AG11728) 购自艾克瑞生物科技有限公司; Hieff® qPCR SYBR® Green Master Mix (Low Rox Plus) (货号: 11202ES08) 购自翌圣生物科技有限公司; 丙氨酸转氨酶(alanine aminotransferase, ALT; 货号: C009-1-1)、天冬氨酸转氨酶(aspartate aminotransferase, AST; 货号: C010-1-1)、TG (货号: A110-1-1)、游离脂肪酸(non-esterified fatty acids, NEFA; 货号: A042-2-1) 试剂盒均购自南京建成生物工程研究所; BCA试剂盒(货号: SB-WB013) 购自上海圣尔生物科技有限公司; 肝脂解酶活力检测试剂盒(货号: BC2385) 购自索莱宝科技有限公司; CPT1A酶活力试剂盒(货号: GMS50118.2.2) 购自上海杰美基因医药科技有限公司; 无脂肪酸BSA (货号: 9048-46-8) 购自大连美仑生物技术有限公司; β-actin抗体(货号: EM2001-07) 购自杭州华安生物技术有限公司; CPT1A抗体(货号: 97361) 购自美国Cell Signaling Technology公司; 胎牛血清(fetal bovine serum, FBS; 货号: 12484028) 购自美国Thermo Fisher Scientific公司; RPMI-1640培养基(货号: 11875093) 购自美国Life Technology公司; 油酸(oleic acid, OA; 货号: M36008)、棕榈酸(palmitic acid, PA; 货号: SLBN0402V) 购自美国Sigma-Aldrich公司。
BioTek Synergy H4酶标仪(美国Biotek公司); QuantStudio 6 flex实时荧光定量PCR仪(美国Life Technology公司); Seahorse XFe 96细胞能量代谢分析仪(美国Agilent Technologies公司)。
药物配制  体内实验药物配制: 精确称取PHY、PGZ粉末于0.5% CMC-Na溶液配制为混悬液; 体外实验药物配制: 精确称取OA原液、PA粉末, 加入DMSO配制为100 mmol·L-1浓度的母液备用; 精确称取PHY粉末, 加入DMSO配制为10 mmol·L-1浓度的母液并梯度稀释备用。
动物实验  C57BL/6小鼠(20 ± 2 g) 购自上海斯莱克实验动物有限责任公司, 实验动物许可证号SCXK (沪) 2022-0004。饲养条件: 温度(22 ± 1) ℃, 湿度65% ± 5%, 12 h光暗循环。小鼠能自由获取食物和水。本动物实验获得上海中医药大学实验动物伦理委员会批准(伦理号: PZSHUTCM190705019)。
MCD饲料诱导NAFLD模型: 35只小鼠被随机分为5组: ① MCS组(n = 7); ② MCD组(n = 7); ③ MCD + PGZ (10 mg·kg-1) 组(n = 7); ④ MCD + PHY (5 mg·kg-1) 组(n = 7); ⑤ MCD + PHY (20 mg·kg-1) 组(n = 7)。小鼠适应性喂养1周后, 进行过渡期饲养: 除了MCS组之外的其他组小鼠第1~2天MCD饲料与MCS饲料以1∶2混合喂养, 第3~4天MCD饲料与MCS饲料等比例混合喂养, 第5~6天MCD饲料与MCS饲料以2∶1混合喂养, 从第7天开始至实验结束, 用MCD饲料喂养。随后, MCS组给予MCS对照饲料, 其余所有小鼠均用MCD喂养6周。MCD饲料正式喂养2周后, 给药4周, 共6周。第3周开始灌胃给予PHY (5和20 mg·kg-1), 阳性药组灌胃给予PGZ (10 mg·kg-1), 每日1次, 直至实验结束, 共4周。实验结束后处死小鼠, 取肝脏及血液用于后续实验。
细胞培养  人正常肝细胞L-02购自中国科学院细胞库, 培养基为含10% FBS、1%双抗的1640培养基, 培养条件为: 37 ℃, 5% CO2, 饱和湿度恒温培养箱, 取对数生长期的细胞用于实验。
ALT、AST检测  取一定量小鼠血清, 按照相关试剂盒说明书进行测定。
肝脏TG和NEFA检测  称取一定量的肝脏样本, 按照说明书检测小鼠肝脏中TG和NEFA含量。
肝脏病理学分析  将小鼠肝脏固定在4%多聚甲醛溶液中, 进行石蜡包埋和切片, 用苏木素-伊红染色(hematoxylin-eosin staining, H & E) 后, 在显微镜下观察肝组织中病理变化。使用天狼星红染色(Sirius red staining) 观察肝脏胶原沉积状况。使用油红O染色(oil red O staining, ORO) 观察肝脏脂肪累积程度。参照文献[19]对小鼠肝脏H & E切片中脂肪变性、小叶炎症和肝细胞气球样变的病变程度进行非酒精性脂肪性肝病活动性评分(NAFLD activity score, NAS) 评分。
荧光实时定量聚合酶链式反应(quantitative real-time polymerase chain reaction, real-time PCR) 检测  按照Trizol试剂盒说明书提取小鼠肝脏组织RNA, 以Evo M-MLV RT Mix Kit with gDNA Clean for qPCR Ver.2试剂盒进行逆转录合成cDNA, 接着将cDNA与Hieff® qPCR SYBR® Green Master Mix混匀后置于QuantStudio 6 flex实时荧光定量PCR仪中进行real-time PCR扩增。扩增完成后, 根据溶解曲线判断扩增反应的准确性。相关基因引物序列见表 1。目标基因的相对表达量以Actin标准化, 并通过2-ΔΔCt方法分析并计算。
Western blot实验  称取10 mg肝脏样本或细胞样本, 加入10倍量的含蛋白酶抑制剂的裂解液冰上匀浆, 提取总蛋白。将制备好的蛋白样本用SDS-PAGE凝胶电泳分离, 在电流作用下转移至聚偏二氟乙烯(polyvinylidene fluoride, PVDF) 膜上, 用5% BSA室温封闭2 h后加入相应的抗体, 4 ℃环境中过夜; 以含0.1% Tween 20的TBST缓冲液洗脱未结合的抗体, 用与辣根过氧化物酶缀合的二抗在室温条件下孵育2 h; 洗脱未结合的二抗, 以化学发光HRP底物对PVDF膜进行显色反应, 置于凝胶成像仪中曝光。
肝脏或L-02细胞CPT1A酶活力检测  取约20 mg肝组织或细胞沉淀, 按试剂盒说明书所述方法制样并检测其中CPT1A蛋白质的酶活力。
免疫荧光检测L-02细胞线粒体损伤  取对数生长期的L-02细胞, 以每孔3×104个细胞铺于24孔板中。待细胞贴壁且生长状态良好时, 将正常组培养基换为无血清含1%无脂肪酸BSA的RPMI-1640培养基, 将模型组及给药组的培养基换为含0.5 mmol·L-1 NEFA、1%无脂肪酸BSA的无血清RPMI-1640培养基, 并在给药组中分别加入10和25 μmol·L-1 PHY。给药24 h后加入Mito-Tracker Red染料, 同时加入Hoechst33342, 避光孵育30 min后荧光显微镜下观察, 并使用Image J统计阳性区域面积。
细胞能量代谢分析  取对数生长期的L-02细胞, 以每孔5×103个细胞铺于Seahorse XF 96孔微孔板中。待细胞贴壁且生长状态良好时, 将细胞培养基更换为含1%无脂肪酸BSA的1640培养基并分组给药, 给药方式同上。给药24 h后, 清洗细胞并将细胞培养基更换为Seahorse XF测定培养基(含2 mmol·L-1 L-谷氨酰胺、1 mmol·L-1丙酮酸钠、25 mmol·L-1葡萄糖), 在37 ℃无CO2培养箱中孵育1 h。将Seahorse XF 96孔微孔板放入Seahorse XFe 96细胞能量代谢仪中连续检测细胞对氧气的消耗速率(oxygen consumption rate, OCR), 随时间依次注射寡霉素(oligomycin; 终浓度为2 μmol·L-1)、碳酰氰-4-三氟甲氧基苯腙[carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, FCCP; 终浓度为0.5 μmol·L-1] 和鱼藤酮或抗霉素A (antimycin A, AA; 终浓度为1 μmol·L-1)。根据试剂盒说明计算L-02细胞线粒体基础呼吸能力、最大呼吸能力、质子漏、ATP合成和储备呼吸能力, 并将线粒体呼吸能力标准化至总细胞数并表示为每5×103个细胞pmol·min-1。
肝脏脂解酶活力测定  称取一定量的肝脏样本, 并按照说明书进行相关操作。
数据处理  实验数据以平均值±标准误(x ± SEM) 表示, 采用SPSS 21.0软件进行统计, 组间用one-way ANOVA统计方法进行方差分析, P < 0.05被认为具有统计学意义。
结果
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1 PHY改善MCD诱导NAFLD小鼠的肝脏损伤
如图 1A所示, MCS组小鼠肝脏中肝细胞规则排布, 无明显脂肪空泡。与MCS组相比, MCD饮食导致小鼠肝脏出现大量脂肪空泡, 并伴随着不同程度的炎性浸润; 而与MCD组相比, 阳性药PGZ (10 mg·kg-1) 和PHY给药组(5和20 mg·kg-1) 都能不同程度地减少肝脏中脂肪空泡。天狼星红染色结果显示, 与MCS组相比, MCD组肝脏内胶原沉积不明显, 而给予PHY (5和20 mg·kg-1) 后也无明显改善作用。肝脏病理学切片NAS评分结果如图 1B所示, PHY治疗4周后能降低NAS评分, 改善肝脏病理学变化(P < 0.05, P < 0.01)。图 1C、D结果提示, PHY (5和20 mg·kg-1) 能降低血清中AST和ALT酶活力, 提示PHY具有改善肝损伤的作用。以上结果说明, PHY (5和20 mg·kg-1) 能减轻肝脏脂肪累积, 减轻肝损伤, 进而改善NAFLD。
2 PHY减轻MCD诱导NAFLD小鼠肝脏中的脂肪累积
如图 2A所示, NAFLD小鼠肝脏油红O染色切片结果显示, 与MCS组相比, MCD组小鼠肝脏中脂肪累积增加, 而阳性药和PHY治疗组均具有降低肝脏脂肪含量的作用, 此结果与H & E染色结果一致。TG结果如图 2B所示, 与MCS组相比, MCD组小鼠肝脏中的TG含量显著升高(P < 0.01), 阳性药有效地降低了肝脏TG含量(P < 0.001), PHY给药后也能显著降低肝脏TG含量(P < 0.01, P < 0.001)。图 2C结果显示, PGZ对于MCD造模后肝脏NEFA含量的上调无显著影响, 而PHY (5和10 mg·kg-1) 均能降低肝脏NEFA含量(P < 0.01, P < 0.05)。以上结果提示, PHY具有改善NAFLD小鼠肝脏中脂肪累积的作用。
3 PHY提升MCD诱导NAFLD小鼠肝脏中CPT1A蛋白表达及酶活力
CPT1A在介导活化长链脂肪酸进入线粒体进行β氧化中具有重要作用[20]。有文献[21]报道肝脏Cpt1a基因治疗能够降低小鼠肝脏脂肪变性程度。因此, 对NAFLD小鼠肝脏Cpt1a mRNA表达进行分析, 如图 3A所示, PHY给药并不影响MCD小鼠肝脏中Cpt1a基因表达水平的下调。Western blot结果显示(图 3B), 与MCS组相比, MCD组CPT1A蛋白水平显著下调(P < 0.01), 而PHY (5和20 mg·kg-1) 给药均能提高CPT1A蛋白表达(P < 0.05, P < 0.01)。
为了确定PHY是否通过介导增强CPT1A酶活力, 促进脂肪酸β氧化进而增加脂肪酸代谢。本研究接着检测了NAFLD肝脏中CPT1A酶活力, 结果如图 3C所示, 与MCD组相比, PHY (5和20 mg·kg-1) 给药均能提升CPT1A酶活力(P < 0.01)。同时, 本研究还检测了NAFLD小鼠肝脏中β氧化相关基因的表达, 如图 3D所示, 与MCD组相比, PHY (5和20 mg·kg-1) 均能不同程度地提高酰基辅酶A脱氢酶超长链[acyl-coenzyme A (acyl-CoA) dehydrogenase very long chain, Acadvl]、酰基辅酶A脱氢酶长链(acyl-CoA dehydrogenase long chain, Acadl)、酰基辅酶A脱氢酶中链(acyl-CoA dehydrogenase medium chain, Acadm)、酰基辅酶A脱氢酶短链(acyl-CoA dehydrogenase short chain, Acads) 的基因表达水平(P < 0.05, P < 0.01, P < 0.001)。以上结果说明, PHY能够增加NAFLD小鼠肝脏CPT1A蛋白表达, 提升CPT1A酶活力, 促进NAFLD小鼠肝脏中脂肪酸的β氧化。
4 PHY提升NEFA刺激的肝细胞内CPT1A蛋白及酶活力
在体外采用0.5 mmol·L-1 NEFA刺激L-02细胞24 h作为细胞模型。如图 4A所示, 在NEFA刺激后, L-02细胞中CPT1A的蛋白表达升高(P < 0.05), 而孵育PHY (25 μmol·L-1) 能进一步提升CPT1A表达水平(P < 0.05)。细胞CPT1A酶活力结果(图 4B) 提示, PHY (10和25 μmol·L-1) 均能显著提高CPT1A酶活力(P < 0.05)。以上结果提示, PHY在体外也能提高CPT1A蛋白表达水平及其酶活力。
5 PHY改善NAFLD病变中肝细胞线粒体功能障碍
CPT1A位于线粒体, 是脂肪酸β氧化的关键限速酶。根据上述结果可知, PHY具有提升CPT1A酶活力, 促进线粒体β氧化, 减少NAFLD小鼠肝脏中的脂质累积的潜力。那么PHY是否还能改善线粒体功能？接着采用免疫荧光手段对L-02细胞进行染色, Mito-Tracker结果如图 5A所示, NEFA刺激后L-02细胞内线粒体膜电位显著下降(P < 0.001), 25 μmol·L-1 PHY能显著提高L-02细胞中降低的线粒体膜电位(P < 0.05)。在体外使用Seahorse XFe96细胞能量代谢分析仪检测NEFA刺激及给药后L-02细胞的线粒体功能。结果如图 5B所示, NEFA刺激后L-02细胞中线粒体基础呼吸能力、最大呼吸能力、储备呼吸能力和ATP合成能力均显著降低(P < 0.05, P < 0.01, P < 0.001), 而给予PHY (10和25 μmol·L-1) 能显著逆转NEFA诱导的线粒体基础呼吸能力、最大呼吸能力和ATP合成能力的降低(P < 0.05, P < 0.01), 同时仅有PHY (25 μmol·L-1) 能显著逆转NEFA诱导的储备呼吸能力降低(P < 0.05)。但不同浓度的PHY (10和25 μmol·L-1) 对NEFA引发的线粒体质子漏水平均无改善作用。线粒体mtDNA水平检测及线粒体生物发生相关基因表达分析的结果显示(图 5C、D), PHY并不影响肝细胞线粒体生成, 即对肝细胞中线粒体总量没有影响。此结果提示, PHY具有提高线粒体膜电位, 改善线粒体功能障碍的作用。
6 PHY促进MCD诱导NAFLD小鼠肝脏中脂解酶活力
除促进脂肪酸β氧化外, 调节脂肪酶活性同样对脂肪分解代谢具有重要作用。如图 6A所示, PHY对脂肪酶A (lipase A, Lipa) 基因表达无明显影响, 而PHY (5和20 mg·kg-1) 能逆转MCD饲料诱导的脂肪酶C (lipase C, Lipc) 基因表达的降低(P < 0.05)。如图 6B所示, 与MCD组相比, PHY (5和20 mg·kg-1) 均能显著提高NAFLD小鼠肝脏中脂肪酶的活性(P < 0.01)。上述结果提示, PHY可能通过增加肝脏脂解酶的表达, 增加其含量并提高脂解酶活性, 进而促进甘油三酯的分解。
讨论
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随着人们生活水平的提高以及生活方式的改变, 全世界范围内NAFLD的患病率逐年升高。据预测, 到2023年, 全世界范围内约有29.8%的人口患有NAFLD[6, 22]。NAFLD已成为全球最常见的慢性肝病之一, 如得不到及时干预, 将导致其最终发展为终末期肝病, 严重威胁患者生命健康。目前, 临床上尚无安全有效的NAFLD治疗药物。因此, 针对NAFLD的新药研发是当前亟需解决的问题之一。
NAFLD最主要的病征是肝脏脂肪蓄积, 其一方面加剧了脂质过氧化产物的生成, 另一方面引发氧化损伤和炎症的级联反应[23, 24], 由此可以发现减少脂肪累积是延缓NAFLD恶化的重要手段之一。通过分析小鼠肝脏病理切片, 本研究发现MCD饲养6周能够使小鼠肝脏出现与临床NAFLD患者相似的病理变化, 即肝脏中出现大量脂肪空泡, 肝细胞排列疏松以边缘不清晰, 并伴有一定程度的炎症反应; 给予PHY (5和20 mg·kg-1) 治疗4周能够显著改善肝脏病理学变化, 主要表现为肝脏中脂肪空泡明显减少, 同时通过对肝脏中TG及NEFA定量检测, 发现PHY给药后能显著降低肝脏脂肪含量。病理切片及生化指标结果均提示PHY具有改善肝脏脂肪堆积的作用。
肝脏脂肪酸代谢主要依赖线粒体脂肪酸β氧化[25], 短链脂肪酸主要通过扩散的方式进入线粒体, 大部分长链脂肪酸需要借助于CPT家族转运至线粒体中, 进而参与β氧化, 因此被认为是β氧化的限速酶[26]。已有研究指出抑制CPT1A能促进NAFLD进程[27], 而激活CPT1A则能有效地改善肝细胞的脂质累积[28]。Western blot结果表明PHY能提升CPT1A蛋白表达水平, 而其对NAFLD小鼠肝脏Cpt1a基因表达水平并无影响, 提示PHY并不是通过影响CPT1A的转录水平进而影响脂肪酸β氧化。CPT1A以酶促反应的方式参与到线粒体β氧化反应中, 酶活力是其发挥作用的关键因素。CPT1A酶活力的结果显示, PHY能提高其酶活力。酰基辅酶A脱氢酶参与线粒体β氧化过程中第一次脱氢反应[29], 影响β氧化的起始环节。Real-time PCR结果提示, PHY给药组均能提高Acadvl等基因表达。综合体内结果可知, PHY可能是通过提高CPT1A蛋白表达及增强其酶活力, 促进线粒体β氧化相关基因表达, 改善肝脏脂肪酸代谢。在体外采用OA∶PA=2∶1的0.5 mmol·L-1 NEFA刺激L-02细胞作为NAFLD的体外模型, CPT1A蛋白及酶活力结果均显示出PHY在体外也具有与体内一致的作用。以上结果提示, PHY具有调节CPT1A促进肝脏脂肪酸β氧化, 改善NAFLD的作用。
临床上, NAFLD患者肝组织中往往表现出不同程度的线粒体损伤、呼吸链活性下降、ROS过量生成、线粒体DNA缺失等[30]。线粒体功能缺失与NAFLD之间存在密切的关系[31], 有研究表明肝脏线粒体是治疗NAFLD的一个重要潜在靶点[32]。现阶段针对线粒体的治疗手段主要包括: 增加线粒体数量和提高线粒体功能[33]。Mito-tracker red荧光结果显示NEFA会导致线粒体膜电位降低, 即脂肪酸能诱导线粒体损伤; 而PHY (25 μmol·L-1) 能够逆转这种线粒体损伤。Seahorse结果提示, PHY (25 μmol·L-1) 给药后能提升线粒体基础呼吸能力、最大呼吸能力、储备呼吸能力和ATP合成能力, 但是其对线粒体质子漏无改善作用, 此结果提示, PHY能改善线粒体功能, 促进线粒体有氧呼吸, 增加ATP的合成, 但PHY对线粒体将能量转化为热能无明显影响。通过检测线粒体mtDNA, 发现PHY并不能提高线粒体mtDNA水平, 对调控线粒体生物发生相关基因进行检测得到相同的结果, 即PHY不能增加线粒体数量。β氧化的底物主要是游离脂肪酸, 肝脏中游离脂肪酸主要由脂肪酶将TG脂解为游离脂肪酸及甘油[27], 本研究通过检测NAFLD小鼠肝脏脂肪酶相关基因及酶活力发现, PHY给药后基因表达和脂解酶活力均上调, 提示PHY可能通过提高肝脏脂解酶基因表达、提高其酶活力, 促进TG分解。以上结果提示, PHY可逆转MCD造模小鼠肝脏中的线粒体损伤, 改善线粒体功能, 促进肝脏中脂肪酸的β氧化代谢, 还能够提高脂解酶活力, 促进肝脏中TG的分解。
综上所述, 本研究发现大黄素甲醚可以提升肝脏脂解酶活性, 加速NAFLD病变肝脏中TG的分解代谢; 抑制线粒体损伤, 改善线粒体功能, 提升CPT1A酶活力, 加速线粒体中脂肪酸的β氧化代谢, 降低肝脏脂质堆积, 改善NAFLD病变。本研究为大黄素甲醚作为NAFLD防治药物的进一步研发奠定了基础。
作者贡献: 张进宇负责完成各种检测实验、采集数据、分析数据和撰写文章; 张少波负责动物实验和分析数据; 徐红负责指导实验方案; 欧阳豪负责指导实验方案和文章的修改; 季莉莉负责指导实验方案、文章的审阅和修改、提供实验经费。
利益冲突: 本研究与任何组织和个人均不存在利益冲突。
基金
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  • 国家自然科学基金资助项目(82273994)
  • 国家自然科学基金资助项目(82173958)
文献
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参考文献 引证文献
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doi: 10.16438/j.0513-4870.2023-1158
  • 接收时间：2023-10-11
  • 首发时间：2025-11-28
  • 出版时间：2024-04-12
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  • 收稿日期：2023-10-11
  • 修回日期：2023-11-14
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国家自然科学基金资助项目(82273994)
国家自然科学基金资助项目(82173958)
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    1.上海中医药大学中药研究所, 中药标准化教育部重点实验室, 中药新资源与质量标准综合评价国家中医药管理局重点研究室, 上海市复方中药重点实验室, 上海 201203
    2.上海中医药大学附属岳阳中西医结合医院肝病科, 上海 201203

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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