23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9
23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2020-03, Vol.41 (3), p.327-335 |
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| creator | Li, Hui-hui Li, Jun Zhang, Xian-jing Li, Jiao-meng Xi, Cong Wang, Wen-qiong Lu, You-li Xuan, Li-jiang |
| description | 23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1–5 μM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) dose-dependently enhanced
LDLR
promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited
PCSK9
(proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg
−1
⋅ d
−1
, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development. |
| doi_str_mv | 10.1038/s41401-019-0274-0 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7471448</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2356706311</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-16418fcb14473115059ef93daee8a91e426a58b4c89c48f2368c8b42735b1a993</originalsourceid><addsrcrecordid>eNp1UU1v3CAURFGjJE3yA3KpkHoNCQ-wgUuldtOmUVdq1I8zwhhviLzGBTvS_vuy2ny0h5xg9ObNzNMgdAb0AihXl1mAoEAoaEKZFITuoSOQoiKSVeJN-dcSiKCKH6K3Od9TyhkHfYAOOfBKKa2OUGD8nAlyFe42bYpudnNqwmRdGPAnPKa4jpPPuA9jaLHrvU12cB43G9zOtsdTgdmlME4hDgUnv5p7uwU4dnh5tfyB7dDi28XPb_oE7Xe2z_708T1Gv798_rX4Spbfr28WH5fECUknArUA1bkGhJAcoKKV9p3mrfVeWQ1esNpWqhFOaSdUx3itXIFM8qoBqzU_Rh92uuPcrH3r_FBS9mZMYW3TxkQbzP-TIdyZVXwwUshiqorA-0eBFP_MPk_mPs6pnJcN41UtaV1yFRbsWC7FnJPvnh2Amm07ZteOKe2YbTuGlp13_0Z73niqoxDYjpDLaFj59GL9uupfQW-aLQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2356706311</pqid></control><display><type>article</type><title>23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9</title><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Li, Hui-hui ; Li, Jun ; Zhang, Xian-jing ; Li, Jiao-meng ; Xi, Cong ; Wang, Wen-qiong ; Lu, You-li ; Xuan, Li-jiang</creator><creatorcontrib>Li, Hui-hui ; Li, Jun ; Zhang, Xian-jing ; Li, Jiao-meng ; Xi, Cong ; Wang, Wen-qiong ; Lu, You-li ; Xuan, Li-jiang</creatorcontrib><description>23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1–5 μM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) dose-dependently enhanced
LDLR
promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited
PCSK9
(proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg
−1
⋅ d
−1
, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-019-0274-0</identifier><identifier>PMID: 31358898</identifier><language>eng</language><publisher>Singapore: Springer Singapore</publisher><subject>Administration, Oral ; Animals ; Antiviral agents ; Biomedical and Life Sciences ; Biomedicine ; Cell Survival - drug effects ; Cholesterol ; Cricetinae ; Dose-Response Relationship, Drug ; Drug development ; Gene regulation ; Hep G2 Cells ; HIV ; Human immunodeficiency virus ; Humans ; Immunology ; Inflammation ; Internal Medicine ; Kexin ; Kinases ; LDLR protein ; Lipid Metabolism - drug effects ; Liver ; Low density lipoprotein ; Low density lipoprotein receptors ; Medical Microbiology ; Molecular Conformation ; Nuclei ; Pharmacology/Toxicology ; Plant Roots - chemistry ; Proprotein Convertase 9 - antagonists & inhibitors ; Proprotein Convertase 9 - genetics ; Proprotein Convertase 9 - metabolism ; Proprotein convertases ; Proteins ; Receptor density ; Receptors, LDL - genetics ; Receptors, LDL - metabolism ; Sterol regulatory element-binding protein ; Structure-Activity Relationship ; Subtilisin ; Transcription ; Trichosanthes - chemistry ; Triterpenes - administration & dosage ; Triterpenes - isolation & purification ; Triterpenes - pharmacology ; Tumor Cells, Cultured ; Vaccine</subject><ispartof>Acta pharmacologica Sinica, 2020-03, Vol.41 (3), p.327-335</ispartof><rights>CPS and SIMM 2019</rights><rights>2019© CPS and SIMM 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-16418fcb14473115059ef93daee8a91e426a58b4c89c48f2368c8b42735b1a993</citedby><cites>FETCH-LOGICAL-c470t-16418fcb14473115059ef93daee8a91e426a58b4c89c48f2368c8b42735b1a993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471448/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471448/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31358898$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Hui-hui</creatorcontrib><creatorcontrib>Li, Jun</creatorcontrib><creatorcontrib>Zhang, Xian-jing</creatorcontrib><creatorcontrib>Li, Jiao-meng</creatorcontrib><creatorcontrib>Xi, Cong</creatorcontrib><creatorcontrib>Wang, Wen-qiong</creatorcontrib><creatorcontrib>Lu, You-li</creatorcontrib><creatorcontrib>Xuan, Li-jiang</creatorcontrib><title>23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1–5 μM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) dose-dependently enhanced
LDLR
promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited
PCSK9
(proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg
−1
⋅ d
−1
, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antiviral agents</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Survival - drug effects</subject><subject>Cholesterol</subject><subject>Cricetinae</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug development</subject><subject>Gene regulation</subject><subject>Hep G2 Cells</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Internal Medicine</subject><subject>Kexin</subject><subject>Kinases</subject><subject>LDLR protein</subject><subject>Lipid Metabolism - drug effects</subject><subject>Liver</subject><subject>Low density lipoprotein</subject><subject>Low density lipoprotein receptors</subject><subject>Medical Microbiology</subject><subject>Molecular Conformation</subject><subject>Nuclei</subject><subject>Pharmacology/Toxicology</subject><subject>Plant Roots - chemistry</subject><subject>Proprotein Convertase 9 - antagonists & inhibitors</subject><subject>Proprotein Convertase 9 - genetics</subject><subject>Proprotein Convertase 9 - metabolism</subject><subject>Proprotein convertases</subject><subject>Proteins</subject><subject>Receptor density</subject><subject>Receptors, LDL - genetics</subject><subject>Receptors, LDL - metabolism</subject><subject>Sterol regulatory element-binding protein</subject><subject>Structure-Activity Relationship</subject><subject>Subtilisin</subject><subject>Transcription</subject><subject>Trichosanthes - chemistry</subject><subject>Triterpenes - administration & dosage</subject><subject>Triterpenes - isolation & purification</subject><subject>Triterpenes - pharmacology</subject><subject>Tumor Cells, Cultured</subject><subject>Vaccine</subject><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1UU1v3CAURFGjJE3yA3KpkHoNCQ-wgUuldtOmUVdq1I8zwhhviLzGBTvS_vuy2ny0h5xg9ObNzNMgdAb0AihXl1mAoEAoaEKZFITuoSOQoiKSVeJN-dcSiKCKH6K3Od9TyhkHfYAOOfBKKa2OUGD8nAlyFe42bYpudnNqwmRdGPAnPKa4jpPPuA9jaLHrvU12cB43G9zOtsdTgdmlME4hDgUnv5p7uwU4dnh5tfyB7dDi28XPb_oE7Xe2z_708T1Gv798_rX4Spbfr28WH5fECUknArUA1bkGhJAcoKKV9p3mrfVeWQ1esNpWqhFOaSdUx3itXIFM8qoBqzU_Rh92uuPcrH3r_FBS9mZMYW3TxkQbzP-TIdyZVXwwUshiqorA-0eBFP_MPk_mPs6pnJcN41UtaV1yFRbsWC7FnJPvnh2Amm07ZteOKe2YbTuGlp13_0Z73niqoxDYjpDLaFj59GL9uupfQW-aLQ</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Li, Hui-hui</creator><creator>Li, Jun</creator><creator>Zhang, Xian-jing</creator><creator>Li, Jiao-meng</creator><creator>Xi, Cong</creator><creator>Wang, Wen-qiong</creator><creator>Lu, You-li</creator><creator>Xuan, Li-jiang</creator><general>Springer Singapore</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20200301</creationdate><title>23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9</title><author>Li, Hui-hui ; Li, Jun ; Zhang, Xian-jing ; Li, Jiao-meng ; Xi, Cong ; Wang, Wen-qiong ; Lu, You-li ; Xuan, Li-jiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-16418fcb14473115059ef93daee8a91e426a58b4c89c48f2368c8b42735b1a993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antiviral agents</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cell Survival - drug effects</topic><topic>Cholesterol</topic><topic>Cricetinae</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug development</topic><topic>Gene regulation</topic><topic>Hep G2 Cells</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Internal Medicine</topic><topic>Kexin</topic><topic>Kinases</topic><topic>LDLR protein</topic><topic>Lipid Metabolism - drug effects</topic><topic>Liver</topic><topic>Low density lipoprotein</topic><topic>Low density lipoprotein receptors</topic><topic>Medical Microbiology</topic><topic>Molecular Conformation</topic><topic>Nuclei</topic><topic>Pharmacology/Toxicology</topic><topic>Plant Roots - chemistry</topic><topic>Proprotein Convertase 9 - antagonists & inhibitors</topic><topic>Proprotein Convertase 9 - genetics</topic><topic>Proprotein Convertase 9 - metabolism</topic><topic>Proprotein convertases</topic><topic>Proteins</topic><topic>Receptor density</topic><topic>Receptors, LDL - genetics</topic><topic>Receptors, LDL - metabolism</topic><topic>Sterol regulatory element-binding protein</topic><topic>Structure-Activity Relationship</topic><topic>Subtilisin</topic><topic>Transcription</topic><topic>Trichosanthes - chemistry</topic><topic>Triterpenes - administration & dosage</topic><topic>Triterpenes - isolation & purification</topic><topic>Triterpenes - pharmacology</topic><topic>Tumor Cells, Cultured</topic><topic>Vaccine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Hui-hui</creatorcontrib><creatorcontrib>Li, Jun</creatorcontrib><creatorcontrib>Zhang, Xian-jing</creatorcontrib><creatorcontrib>Li, Jiao-meng</creatorcontrib><creatorcontrib>Xi, Cong</creatorcontrib><creatorcontrib>Wang, Wen-qiong</creatorcontrib><creatorcontrib>Lu, You-li</creatorcontrib><creatorcontrib>Xuan, Li-jiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Hui-hui</au><au>Li, Jun</au><au>Zhang, Xian-jing</au><au>Li, Jiao-meng</au><au>Xi, Cong</au><au>Wang, Wen-qiong</au><au>Lu, You-li</au><au>Xuan, Li-jiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>41</volume><issue>3</issue><spage>327</spage><epage>335</epage><pages>327-335</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1–5 μM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) dose-dependently enhanced
LDLR
promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited
PCSK9
(proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg
−1
⋅ d
−1
, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.</abstract><cop>Singapore</cop><pub>Springer Singapore</pub><pmid>31358898</pmid><doi>10.1038/s41401-019-0274-0</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta pharmacologica Sinica, 2020-03, Vol.41 (3), p.327-335 |
| issn | 1671-4083 1745-7254 |
| language | eng |
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| source | MEDLINE; PubMed Central; Alma/SFX Local Collection |
| subjects | Administration, Oral Animals Antiviral agents Biomedical and Life Sciences Biomedicine Cell Survival - drug effects Cholesterol Cricetinae Dose-Response Relationship, Drug Drug development Gene regulation Hep G2 Cells HIV Human immunodeficiency virus Humans Immunology Inflammation Internal Medicine Kexin Kinases LDLR protein Lipid Metabolism - drug effects Liver Low density lipoprotein Low density lipoprotein receptors Medical Microbiology Molecular Conformation Nuclei Pharmacology/Toxicology Plant Roots - chemistry Proprotein Convertase 9 - antagonists & inhibitors Proprotein Convertase 9 - genetics Proprotein Convertase 9 - metabolism Proprotein convertases Proteins Receptor density Receptors, LDL - genetics Receptors, LDL - metabolism Sterol regulatory element-binding protein Structure-Activity Relationship Subtilisin Transcription Trichosanthes - chemistry Triterpenes - administration & dosage Triterpenes - isolation & purification Triterpenes - pharmacology Tumor Cells, Cultured Vaccine |
| title | 23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9 |
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