| First Author | Shende VR | Year | 2015 |
| Journal | J Lipid Res | Volume | 56 |
| Issue | 4 | Pages | 801-9 |
| PubMed ID | 25652089 | Mgi Jnum | J:331029 |
| Mgi Id | MGI:6870893 | Doi | 10.1194/jlr.M052969 |
| Citation | Shende VR, et al. (2015) Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1alpha in normolipidemic mice. J Lipid Res 56(4):801-9 |
| abstractText | The transcription factors hepatic nuclear factor (HNF)1alpha and HNF1beta 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-shHNF1alpha and Ad-shHNF1beta) to examine the effects of knockdown of HNF1alpha or HNF1beta 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-shHNF1alpha, but not Ad-shHNF1beta, markedly reduced PCSK9 mRNA expression in HepG2 cells with a concomitant increase in LDLR protein abundance. Injecting Ad-shHNF1alpha in mice fed a normal diet significantly ( approximately 50%) reduced liver mRNA expression and serum concentration of PCSK9 with a concomitant increase ( approximately 1.9-fold) in hepatic LDLR protein abundance. Furthermore, we observed a modest but significant reduction in circulating LDL cholesterol after knockdown of HNF1alpha in these normolipidemic mice. Consistent with the observation that knockdown of HNF1beta did not affect PCSK9 mRNA or protein expression in cultured hepatic cells, Ad-shHNF1beta infection in mice resulted in no change in the hepatic mRNA expression or serum content of PCSK9. Altogether, our study demonstrates that HNF1alpha, but not HNF1beta, is the primary positive regulator of PCSK9 transcription in mouse liver. |
