Up-regulation of low-density lipoprotein receptor in human hepatocytes is induced by sequestration of free cholesterol in the endosomal/lysosomal compartment
Biochemical Pharmacology, ISSN: 0006-2952, Vol: 67, Issue: 12, Page: 2281-2289
2004
- 27Citations
- 20Captures
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Metrics Details
- Citations27
- Citation Indexes27
- 27
- CrossRef21
- Captures20
- Readers20
- 20
Article Description
Up-regulation of low-density lipoprotein receptor (LDLr) is a key mechanism to control elevated plasma LDL-cholesterol levels. In the present paper, we compare the ability of four distinct pharmacological drugs to up-regulate LDLr expression in human hepatocytes. HepG2 cells were treated with the steroidal analog GW707, the oxidosqualene cyclase inhibitor U18666A, the 3β-hydroxysterol Δ 7 -reductase inhibitor AY-9944 and the vacuolar-type ATPase inhibitor bafilomycin A1. We found that the four compounds induced sequestration of free cholesterol in the endosomal/lysosomal compartment leading to a positive filipin staining pattern and a complete inhibition of cholesteryl ester synthesis. As a consequence of the sequestration of cholesterol, the expression and the activity of LDLr were strongly induced resulting from a transcriptional effect which was measured by a reporter gene assay. These effects were fully abolished when an exogenous water soluble cholesterol analog was added to the cells. These findings have led to the identification of a common mechanism to up-regulate LDLr expression in human hepatocytes and may represent an interesting alternative approach to identify new hypolipidemic drugs.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0006295204001820; http://dx.doi.org/10.1016/j.bcp.2004.03.006; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=2442480496&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/15163559; http://linkinghub.elsevier.com/retrieve/pii/S0006295204001820; http://dx.doi.org/10.1016/s0006-2952(04)00182-0; https://linkinghub.elsevier.com/retrieve/pii/S0006295204001820; https://dx.doi.org/10.1016/j.bcp.2004.03.006
Elsevier BV
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