Abstract
Phospholipid transfer protein (PLTP) plays an important role in atherogenesis and lipoprotein metabolism. PLTP exerts its functions intracellularly and extracellularly. Both PLTP and microsomal triglyceride transfer protein (MTP) have been shown to regulate the secretion of apolipoprotein B (apoB) in hepatocytes. We have previously reported the characterization of inhibitors that selectively inhibit PLTP activity and reduce apoB secretion in hepatocytes. In the present study, we identified more compounds that inhibit both PLTP and MTP activity to various extents. These dual inhibitors are structurally different from the PLTP-selective inhibitors. In human hepatoma cell lines, dual inhibitors seem to be more effective in reducing apoB secretion than selective PLTP or MTP inhibitors. Furthermore, the dual inhibitors markedly reduced triglyceride secretion from hepatocytes. In the absence of PLTP, the dual inhibitors can further reduce apoB secretion, whereas selective PLTP inhibitors had no effect. We conclude that MTP and PLTP may work coordinately in the process of hepatic apoB assembly and secretion. To avoid liver toxicity mediated by MTP inhibition, selective PLTP inhibitors should be pursued.
Footnotes
This work was partially supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL-69817] (to X.-C.J.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171942.
-
ABBREVIATIONS:
- PLTP
- phospholipid transfer protein
- CETP
- cholesteryl ester transfer protein
- LDL
- low-density lipoprotein
- MTP
- microsomal triglyceride transfer protein
- apoB
- apolipoprotein B
- DMSO
- dimethyl sulfoxide
- ELISA
- enzyme-linked immunosorbent assay
- MTT
- 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide
- DMEM
- Dulbecco's modified Eagle's medium
- BSA
- bovine serum albumin.
- Received June 25, 2010.
- Accepted August 26, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|