Identification and characterization of dual inhibitors for phospholipid transfer protein and microsomal triglyceride transfer protein.
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.
Luo
Yi
Y
Department of Cardiovascular Metabolic and Endocrine Disease, Pfizer Global Research Division, Pfizer Inc, Groton,Connecticut 06340, USA. yi.luo@pfizer.com
Shelly
Lorraine
L
Sand
Thomas
T
Chang
George
G
Jiang
Xian-Cheng
XC
D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D053283:Apolipoprotein B-48 / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D053440:Lipoproteins, HDL3 / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014304:Triolein / Q000378:metabolism
D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D002352:Carrier Proteins; D000960:Hypolipidemic Agents; D053440:Lipoproteins, HDL3; D008081:Liposomes; C493430:PLTP protein, human; D010713:Phosphatidylcholines; D049294:Phospholipid Transfer Proteins; D011994:Recombinant Proteins; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C510091:phospholipid transfer protein, mouse; D014304:Triolein
J Lipid Res. 1998 Jul;39(7):1448-54
9684748
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1601-7
12855484
J Biol Chem. 2000 Sep 29;275(39):30372-7
10893406
Nat Med. 2001 Jul;7(7):847-52
11433351
Biochim Biophys Acta. 1998 Aug 14;1404(1-2):85-100
9714753
Diabetologia. 2006 Feb;49(2):398-404
16374627
PLoS One. 2008 May 28;3(5):e2255
18509527
J Lipid Res. 1985 Jul;26(7):842-51
4031662
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11991-5
8876250
J Pharmacol Exp Ther. 2010 Mar;332(3):1100-6
19933370
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1484-5
12972459
J Biol Chem. 2006 Apr 21;281(16):11019-27
16478722
J Lipid Res. 2003 Oct;44(10):1887-901
12837854
J Biol Chem. 2005 May 6;280(18):18336-40
15734742
J Biol Chem. 2002 Dec 13;277(50):48938-43
12372822
J Lipid Res. 1996 Jul;37(7):1468-80
8827519
J Lipid Res. 1998 Aug;39(8):1543-57
9717714
J Lipid Res. 2005 Aug;46(8):1779-85
15897609
J Biol Chem. 1994 Mar 25;269(12):9388-91
8132678
Front Biosci. 2003 May 01;8:s500-6
12700048
Arterioscler Thromb Vasc Biol. 2003 Oct 1;23(10):1857-62
12947020
J Lipid Res. 2008 Dec;49(12):2504-12
18711210
J Lipid Res. 2004 Apr;45(4):764-72
14754905
J Lipid Res. 1988 Dec;29(12):1593-602
2854151