Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S]
The transcription factors hepatic nuclear factor (HNF)1α and HNF1β can bind to the HNF1 site on the proprotein convertase subtilisin/kexin type 9 (PCSK9) promoter to activate transcription in HepG2 cells. However, it is unknown whether one or both HNF1 factors are obligatory for transactivating hepa...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-04-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520355620 |
| _version_ | 1818601430571810816 |
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| author | Vikram Ravindra Shende Minhao Wu Amar Bahadur Singh Bin Dong Chin Fung Kelvin Kan Jingwen Liu |
| author_facet | Vikram Ravindra Shende Minhao Wu Amar Bahadur Singh Bin Dong Chin Fung Kelvin Kan Jingwen Liu |
| author_sort | Vikram Ravindra Shende |
| collection | DOAJ |
| description | The transcription factors hepatic nuclear factor (HNF)1α and HNF1β can bind to the HNF1 site on the proprotein convertase subtilisin/kexin type 9 (PCSK9) promoter to activate transcription in HepG2 cells. However, it is unknown whether one or both HNF1 factors are obligatory for transactivating hepatic PCSK9 gene expression in vivo. We developed shRNA adenoviral constructs (Ad-shHNF1α and Ad-shHNF1β) to examine the effects of knockdown of HNF1α or HNF1β on PCSK9 expression and its consequent impact on LDL receptor (LDLR) protein levels in cultured hepatic cells and liver tissue. We demonstrated that infection with Ad-shHNF1α, but not Ad-shHNF1β, markedly reduced PCSK9 mRNA expression in HepG2 cells with a concomitant increase in LDLR protein abundance. Injecting Ad-shHNF1α in mice fed a normal diet significantly (∼50%) reduced liver mRNA expression and serum concentration of PCSK9 with a concomitant increase (∼1.9-fold) in hepatic LDLR protein abundance. Furthermore, we observed a modest but significant reduction in circulating LDL cholesterol after knockdown of HNF1α in these normolipidemic mice. Consistent with the observation that knockdown of HNF1β did not affect PCSK9 mRNA or protein expression in cultured hepatic cells, Ad-shHNF1β infection in mice resulted in no change in the hepatic mRNA expression or serum content of PCSK9. Altogether, our study demonstrates that HNF1α, but not HNF1β, is the primary positive regulator of PCSK9 transcription in mouse liver. |
| first_indexed | 2024-12-16T12:51:16Z |
| format | Article |
| id | doaj.art-7cd9eb0c5d6441ccb0771398690bff49 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-16T12:51:16Z |
| publishDate | 2015-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-7cd9eb0c5d6441ccb0771398690bff492022-12-21T22:31:08ZengElsevierJournal of Lipid Research0022-22752015-04-01564801809Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S]Vikram Ravindra Shende0Minhao Wu1Amar Bahadur Singh2Bin Dong3Chin Fung Kelvin Kan4Jingwen Liu5Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; Department of Medicine, Stanford University, Stanford, CA 94305Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; Department of Medicine, Stanford University, Stanford, CA 94305Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304To whom correspondence should be addressed; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; To whom correspondence should be addressedThe transcription factors hepatic nuclear factor (HNF)1α and HNF1β can bind to the HNF1 site on the proprotein convertase subtilisin/kexin type 9 (PCSK9) promoter to activate transcription in HepG2 cells. However, it is unknown whether one or both HNF1 factors are obligatory for transactivating hepatic PCSK9 gene expression in vivo. We developed shRNA adenoviral constructs (Ad-shHNF1α and Ad-shHNF1β) to examine the effects of knockdown of HNF1α or HNF1β on PCSK9 expression and its consequent impact on LDL receptor (LDLR) protein levels in cultured hepatic cells and liver tissue. We demonstrated that infection with Ad-shHNF1α, but not Ad-shHNF1β, markedly reduced PCSK9 mRNA expression in HepG2 cells with a concomitant increase in LDLR protein abundance. Injecting Ad-shHNF1α in mice fed a normal diet significantly (∼50%) reduced liver mRNA expression and serum concentration of PCSK9 with a concomitant increase (∼1.9-fold) in hepatic LDLR protein abundance. Furthermore, we observed a modest but significant reduction in circulating LDL cholesterol after knockdown of HNF1α in these normolipidemic mice. Consistent with the observation that knockdown of HNF1β did not affect PCSK9 mRNA or protein expression in cultured hepatic cells, Ad-shHNF1β infection in mice resulted in no change in the hepatic mRNA expression or serum content of PCSK9. Altogether, our study demonstrates that HNF1α, but not HNF1β, is the primary positive regulator of PCSK9 transcription in mouse liver.http://www.sciencedirect.com/science/article/pii/S0022227520355620hepatic nuclear factor 1αhepatic nuclear factor 1βproprotein convertase subtilisin/kexin type 9low density lipoprotein receptorlow density lipoprotein cholesterol |
| spellingShingle | Vikram Ravindra Shende Minhao Wu Amar Bahadur Singh Bin Dong Chin Fung Kelvin Kan Jingwen Liu Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S] Journal of Lipid Research hepatic nuclear factor 1α hepatic nuclear factor 1β proprotein convertase subtilisin/kexin type 9 low density lipoprotein receptor low density lipoprotein cholesterol |
| title | Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S] |
| title_full | Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S] |
| title_fullStr | Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S] |
| title_full_unstemmed | Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S] |
| title_short | Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice[S] |
| title_sort | reduction of circulating pcsk9 and ldl c levels by liver specific knockdown of hnf1α in normolipidemic mice s |
| topic | hepatic nuclear factor 1α hepatic nuclear factor 1β proprotein convertase subtilisin/kexin type 9 low density lipoprotein receptor low density lipoprotein cholesterol |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520355620 |
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