Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
March-2017 Volume 39 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
March-2017 Volume 39 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

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
  • View Affiliations / Copyright

    Affiliations: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA
  • Pages: 749-756
    |
    Published online on: February 6, 2017
       https://doi.org/10.3892/ijmm.2017.2879
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



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.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC and Hobbs HH: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 282:18602–18612. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, Anderson NN, Ho YK, Hammer RE and Horton JD: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 116:2995–3005. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, Patel S, Sullivan DR, Cohn JS, Rye KA and Barter PJ: Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem. 54:1038–1045. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Lakoski SG, Lagace TA, Cohen JC, Horton JD and Hobbs HH: Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab. 94:2537–2543. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Ling H, Burns TL and Hilleman DE: An update on the clinical development of proprotein convertase subtilisin kexin 9 inhibitors, novel therapeutic agents for lowering low-density lipoprotein cholesterol. Cardiovasc Ther. 32:82–88. 2014. View Article : Google Scholar

6 

Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS and Goldstein JL: Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA. 100:12027–12032. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Maxwell KN, Soccio RE, Duncan EM, Sehayek E and Breslow JL: Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J ipid Res. 44:2109–2119. 2003.

8 

Li H, Dong B, Park SW, Lee HS, Chen W and Liu J: Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem. 284:28885–28895. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L and Prat A: Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 24:1454–1459. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D and Park SW: Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res. 49:399–409. 2008. View Article : Google Scholar

11 

Raal F, Panz V, Immelman A and Pilcher G: Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy. J Am Heart Assoc. 2:e0000282013. View Article : Google Scholar : PubMed/NCBI

12 

Dong B, Wu M, Li H, Kraemer FB, Adeli K, Seidah NG, Park SW and Liu J: Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: Mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J Lipid Res. 51:1486–1495. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Costa RH, Kalinichenko VV, Holterman AX and Wang X: Transcription factors in liver development, differentiation, and regeneration. Hepatology. 38:1331–1347. 2003. View Article : Google Scholar : PubMed/NCBI

14 

Mendel DB, Hansen LP, Graves MK, Conley PB and Crabtree R: HNF-1α and HNF-1β (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev. 5:1042–1056. 1991. View Article : Google Scholar : PubMed/NCBI

15 

Ai D, Chen C, Han S, Ganda A, Murphy AJ, Haeusler R, Thorp E, Accili D, Horton JD and Tall AR: Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Invest. 122:1262–1270. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Servitja J-M, Pignatelli M, Maestro MA, Cardalda C, Boj SF, Lozano J, Blanco E, Lafuente A, McCarthy MI, Sumoy L, et al: Hnf1α (MODY3) controls tissue-specific transcriptional programs and exerts opposed effects on cell growth in pancreatic islets and liver. Mol Cell Biol. 29:2945–2959. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Shende VR, Wu M, Singh AB, Dong B, Kan CF and Liu J: Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice. J Lipid Res. 56:801–809. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Dong B, Singh AB, Azhar S, Seidah NG and Liu J: High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels. Atherosclerosis. 239:364–374. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Miao J, Manthena PV, Haas ME, Ling AV, Shin DJ, Graham MJ, Crooke RM, Liu J and Biddinger SB: Role of insulin in the regulation of proprotein convertase subtilisin/kexin type 9. Arterioscler Thromb Vasc Biol. 35:1589–1596. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Hentze H, Jensen KK, Chia SM, Johns DG, Shaw RJ, Davis HR Jr, Shih SJ and Wong KK: Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys: Effects of LDL lowering by ezetimibe in the absence of statins. Atherosclerosis. 231:84–90. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Dong B, Li H, Singh AB, Cao A and Liu J: Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway. J Biol Chem. 290:4047–4058. 2015. View Article : Google Scholar

22 

Cao A, Wu M, Li H and Liu J: Janus kinase activation by cytokine oncostatin M decreases PCSK9 expression in liver cells. J Lipid Res. 52:518–530. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Wu M, Dong B, Cao A, Li H and Liu J: Delineation of molecular pathways that regulate hepatic PCSK9 and LDL receptor expression during fasting in normolipidemic hamsters. Atherosclerosis. 224:401–410. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Verbeek R, Stoekenbroek RM and Hovingh GK; CSK9 inhibitors: Novel therapeutic agents for the treatment of hypercholesterolemia. Eur J Pharmacol. 763:38–47. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Huynh K: Dyslipidaemia. Assessing the efficacy and safety of evolocumab and alirocumab. Nat Rev Cardiol. 12:2612015. View Article : Google Scholar : PubMed/NCBI

26 

Desai NR and Sabatine MS: PCSK9 inhibition in patients with hypercholesterolemia. Trends Cardiovasc Med. 25:567–574. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Yin W, Carballo-Jane E, McLaren DG, Mendoza VH, Gagen K, Geoghagen NS, McNamara LA, Gorski JN, Eiermann GJ, Petrov A, et al: Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia. J Lipid Res. 53:51–65. 2012. View Article : Google Scholar :

28 

Dietschy JM, Turley SD and Spady DK: Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 34:1637–1659. 1993.PubMed/NCBI

29 

Quig DW, Arbeeny CM and Zilversmit DB: Effects of hyperlipidemias in hamsters on lipid transfer protein activity and unidirectional cholesteryl ester transfer in plasma. Biochim Biophys Acta. 1083:257–264. 1991. View Article : Google Scholar : PubMed/NCBI

30 

Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, Lewis GF and Adeli K: Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem. 275:8416–8425. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Harries LW, Brown JE and Gloyn AL: Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes. PLoS One. 4:e78552009. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Dong B, Singh AB, Shende VR and Liu J: Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. Int J Mol Med 39: 749-756, 2017.
APA
Dong, B., Singh, A.B., Shende, V.R., & Liu, J. (2017). Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. International Journal of Molecular Medicine, 39, 749-756. https://doi.org/10.3892/ijmm.2017.2879
MLA
Dong, B., Singh, A. B., Shende, V. R., Liu, J."Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters". International Journal of Molecular Medicine 39.3 (2017): 749-756.
Chicago
Dong, B., Singh, A. B., Shende, V. R., Liu, J."Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters". International Journal of Molecular Medicine 39, no. 3 (2017): 749-756. https://doi.org/10.3892/ijmm.2017.2879
Copy and paste a formatted citation
x
Spandidos Publications style
Dong B, Singh AB, Shende VR and Liu J: Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. Int J Mol Med 39: 749-756, 2017.
APA
Dong, B., Singh, A.B., Shende, V.R., & Liu, J. (2017). Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. International Journal of Molecular Medicine, 39, 749-756. https://doi.org/10.3892/ijmm.2017.2879
MLA
Dong, B., Singh, A. B., Shende, V. R., Liu, J."Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters". International Journal of Molecular Medicine 39.3 (2017): 749-756.
Chicago
Dong, B., Singh, A. B., Shende, V. R., Liu, J."Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters". International Journal of Molecular Medicine 39, no. 3 (2017): 749-756. https://doi.org/10.3892/ijmm.2017.2879
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team