Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters

Dong,Bin; Singh,Amar  Bahadur; Shende,Vikram  Ravindra; Liu,Jingwen

doi:10.3892/ijmm.2017.2879

Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters

Authors:
- Bin Dong
- Amar Bahadur Singh
- Vikram Ravindra Shende
- Jingwen Liu
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Affiliations: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA
Published online on: February 6, 2017 https://doi.org/10.3892/ijmm.2017.2879
Pages: 749-756

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) impedes low‑density lipoprotein (LDL) receptor (LDLR)-mediated LDL-cholesterol uptake and has hence emerged as a critical regulator of serum cholesterol levels and a new therapeutic target for the treatment of hypercholesterolemia. Statins have been shown to elevate circulating PCSK9 levels by stimulating PCSK9 gene transcription, which reduces the clinical efficacy of statin in LDL‑cholesterol reduction. The transcription of PCSK9 is partially controlled by the hepatocyte nuclear factor 1 (HNF1) binding site embedded in the proximal region of its promoter. In this study, we utilized adenoviral shRNA delivery vectors to generate liver-specific knockdown of HNF1α (Ad‑shHNF1α) or HNF1β (Ad‑shHNF1β) in hamsters to examine the impact of reduced hepatic expression of HNF1 transcription factors on statin‑induced elevation of PCSK9 expression and serum cholesterol levels. We showed that the administration of rosuvastatin (RSV) to normolipidemic hamsters significantly augmented hepatic PCSK9 expression and serum PCSK9 levels. In addition, RSV treatment increased hepatic HNF1α protein levels without a clear effect on HNF1α mRNA expression. Injection of Ad-shHNF1α or Ad‑shHNF1β into hamsters both blunted RSV‑induced elevation of PCSK9 serum concentration and hepatic mRNA and protein levels, which led to significant increases in liver LDLR protein abundance. Furthermore, hepatic depletion of HNF1 factors lowered circulating total cholesterol and non‑high density lipoprotein cholesterol levels in RSV‑treated hamsters. Our study demonstrates that both HNF1α and HNF1β are positive regulators of hepatic PCSK9 transcription in hamster species and that transient, liver-specific knockdown of either HNF1α or HNF1β could antagonize the RSV‑induced elevation of serum PCSK9 and reduce circulating cholesterol levels.

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