Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport.
Increased blood cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Cholesterol homeostasis in the body is controlled mainly by endogenous synthesis, intestinal absorption, and hepatic excretion. Niemann-Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It functions as a sterol transporter to mediate intestinal cholesterol absorption and counter-balances hepatobiliary cholesterol excretion. NPC1L1 is the molecular target of ezetimibe, a potent cholesterol absorption inhibitor that is widely used in treating hypercholesterolemia. Recent findings suggest that NPC1L1 deficiency or ezetimibe treatment also prevents diet-induced hepatic steatosis and obesity in addition to reducing blood cholesterol. Future studies should focus on molecular mechanisms underlying NPC1L1-dependent cholesterol transport and elucidation of how a cholesterol transporter modulates the pathogenesis of metabolic diseases.
Jia
Lin
L
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040, USA.
Betters
Jenna L
JL
Yu
Liqing
L
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001384:Azetidines / Q000494:pharmacology; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D000069438:Ezetimibe; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010840:Phytosterols / Q000378:metabolism; D011323:Primates / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D010840:Phytosterols; D002784:Cholesterol; D000069438:Ezetimibe
Liver Int. 2008 Aug;28(7):935-47
18783541
Circulation. 2002 Dec 17;106(25):3143-421
12485966
Gastroenterology. 2007 Sep;133(3):967-75
17854600
J Clin Invest. 1974 Apr;53(4):1033-43
4360855
J Clin Invest. 2006 Apr;116(4):1052-62
16543947
J Biol Chem. 2009 Aug 14;284(33):22481-22490
19542231
Nature. 1996 Oct 24;383(6602):728-31
8878485
Arch Intern Med. 1972 Oct;130(4):552-73
4627839
Biochim Biophys Acta. 2007 Sep;1771(9):1132-9
17442616
N Engl J Med. 2008 Apr 3;358(14):1431-43
18376000
Mol Pharmacol. 2008 Apr;73(4):1072-84
18187582
Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2014-21
17641249
Genomics. 2000 Apr 15;65(2):137-45
10783261
Clin Endocrinol (Oxf). 2008 Jul;69(1):45-51
18031309
J Clin Invest. 1988 Feb;81(2):300-9
2448340
J Clin Endocrinol Metab. 2002 Feb;87(2):423-37
11836262
Biochemistry. 2008 May 6;47(18):5194-204
18402465
J Lipid Res. 2001 Aug;42(8):1214-9
11483622
Circulation. 2004 Jul 13;110(2):227-39
15249516
Mol Pharmacol. 2007 Jan;71(1):19-29
17005902
J Lipid Res. 2007 Feb;48(2):395-404
17114806
J Lipid Res. 2005 Nov;46(11):2423-31
16150828
J Clin Invest. 2007 Jul;117(7):1968-78
17571164
Am J Cardiol. 2002 Nov 15;90(10):1084-91
12423708
J Lipid Res. 1994 Jun;35(6):943-55
8077852
Curr Opin Lipidol. 2003 Jun;14(3):233-40
12840653
Biochem J. 2007 Sep 1;406(2):273-83
17523925
Hepatology. 2007 Oct;46(4):1081-90
17654743
Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G776-83
18718999
Biochim Biophys Acta. 2007 Sep;1771(9):1140-7
17689140
Clin Pharmacol Ther. 2010 Jan;87(1):117-21
19907422
Cell. 2009 Jun 26;137(7):1213-24
19563754
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16237-42
12444248
J Lipid Res. 2006 Dec;47(12):2820-4
16966491
J Clin Invest. 1999 May;103(9):1287-98
10225972
Nutr Metab Cardiovasc Dis. 2010 May;20(4):236-42
19747803
J Lipid Res. 2001 Feb;42(2):170-80
11181745
J Clin Invest. 1964 Feb;43:247-57
14162533
J Nutr. 2006 Aug;136(8):2135-40
16857831
Gastroenterology. 2005 Jan;128(1):147-56
15633131
Science. 2000 Dec 22;290(5500):2295-8
11125140
J Atheroscler Thromb. 2007 Jun;14(3):99-108
17587760
J Hepatol. 2009 Sep;51(3):548-56
19596472
J Atheroscler Thromb. 2010 Feb 26;17(2):173-80
20150722
Nat Genet. 2001 Jan;27(1):79-83
11138003
J Biol Chem. 2006 Sep 22;281(38):27894-904
16867993
J Lipid Res. 2009 Feb;50(2):293-300
18796403
Circulation. 2010 Feb 23;121(7):e46-e215
20019324
J Lipid Res. 2007 Dec;48(12):2725-35
17726195
J Biol Chem. 1998 Oct 9;273(41):26747-54
9756918
Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8132-7
15928087
Hepatology. 2004 Dec;40(6):1387-95
15565570
J Lipid Res. 2002 Nov;43(11):1864-74
12401885
J Biol Chem. 2003 May 2;278(18):15565-70
12601003
J Lipid Res. 1980 Nov;21(8):1058-64
7462801
Clin Genet. 2005 Feb;67(2):175-7
15679830
J Clin Invest. 2004 Jul;114(2):147-52
15254578
J Am Coll Cardiol. 2002 Dec 18;40(12):2125-34
12505224
Mol Cell. 2004 Jul 23;15(2):259-68
15260976
J Lipid Res. 2010 Nov;51(11):3135-44
20699423
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3450-5
14985510
J Lipid Res. 2007 Mar;48(3):699-708
17130282
Curr Opin Gastroenterol. 2009 May;25(3):230-7
19396962
BMC Gastroenterol. 2004 Sep 21;4:21
15383151
Atherosclerosis. 1995 Jun;115(2):135-46
7661873
Science. 1997 Jul 11;277(5323):232-5
9211850
J Clin Invest. 1960 May;39:730-40
13814573
J Lipid Res. 2003 Nov;44(11):2049-58
12897186
J Lipid Res. 2009 Nov;50(11):2235-44
19454765
Brain Res Bull. 1991 Sep-Oct;27(3-4):477-82
1959049
J Med Chem. 1998 Mar 12;41(6):973-80
9526571
Annu Rev Physiol. 2007;69:221-48
17002594
J Lipid Res. 1992 Jul;33(7):945-55
1431587
Hepatology. 2006 Nov;44(5):1259-66
17058264
Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G369-76
17008555
J Biol Chem. 2005 Apr 1;280(13):12710-20
15671032
Metabolism. 2001 Oct;50(10):1234-41
11586500
J Clin Invest. 1970 May;49(5):952-67
5441548
Science. 2004 Feb 20;303(5661):1201-4
14976318
Cell. 1997 May 2;89(3):331-40
9150132
J Biol Chem. 2005 Jan 14;280(2):1306-20
15494415
J Lipid Res. 2006 Oct;47(10):2112-20
16829661
Hepatology. 2003 Jul;38(1):14-7
12829980
Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):448-54
18187667
World J Gastroenterol. 2006 Jul 21;12(27):4369-76
16865780
Gastroenterology. 1999 Jun;116(6):1413-9
10348825
J Biol Chem. 2006 Mar 10;281(10):6616-24
16407187
FEBS Lett. 2010 Jul 2;584(13):2740-7
20307540
Nat Genet. 1996 May;13(1):18-9
8673096
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):841-9
17218600
Hepatol Res. 2010 Jun;40(6):566-73
20412324
J Lipid Res. 2010 Oct;51(10):3024-33
20601625
J Lipid Res. 2008 Sep;49(9):2023-37
18523240
J Lipid Res. 1999 Feb;40(2):302-8
9925660
Pharm Res. 2008 May;25(5):1134-41
18080173
Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G813-22
18718997
Pediatrics. 2006 Oct;118(4):1388-93
17015527
J Lipid Res. 2010 May;51(5):1201-7
19752398
Proc Natl Acad Sci U S A. 1981 Mar;78(3):1396-400
6262794
Trends Genet. 2002 Apr;18(4):193-201
11932020
J Biol Chem. 2005 Jul 29;280(30):28103-9
15919660
J Clin Invest. 2002 Sep;110(5):671-80
12208868
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11140-5
18682566
Cell Metab. 2008 Feb;7(2):95-6
18249166
J Clin Invest. 2002 May;109(9):1125-31
11994399
Annu Rev Biochem. 2003;72:395-447
12651740
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12473-8
15314240
J Clin Lipidol. 2008 Apr;2(2):S20-S28
18496605
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1030-8
19654286
FEBS Lett. 2007 Dec 11;581(29):5664-70
18022391
Science. 2000 Dec 1;290(5497):1771-5
11099417
J Lipid Res. 1993 Oct;34(10):1637-59
8245716
J Biol Chem. 2003 Nov 28;278(48):48275-82
14504269
Cell Metab. 2007 Jul;6(1):69-78
17618857
Br J Pharmacol. 2000 Apr;129(8):1748-54
10780982
Cell Metab. 2008 Jun;7(6):508-19
18522832
Gastroenterology. 1972 Jun;62(6):1200-17
5050318
Annu Rev Nutr. 1983;3:71-96
6357243
Science. 2000 Sep 1;289(5484):1524-9
10968783
Hum Mol Genet. 2008 Jul 15;17(14):2101-7
18413323
Biochem J. 1960 May;74:441-4
13854246
J Lipid Res. 2005 Aug;46(8):1739-44
15930515
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1810-5
16449388
J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S5-10
16540768
Eur J Pharmacol. 2008 Apr 14;584(1):118-24
18329014
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5306-11
11309497
Gastroenterology. 2008 Jun;134(7):2101-10
18442485
Genomics. 2005 Dec;86(6):648-56
16297596
J Lipid Res. 2010 Jun;51(6):1354-62
20460578
Diabetes Care. 2010 May;33(5):1134-9
20185740
J Lipid Res. 2005 Mar;46(3):526-34
15604518
Cell. 1983 May;33(1):273-85
6147196
Atherosclerosis. 2008 May;198(1):77-84
18054357
Biochim Biophys Acta. 2005 Apr 15;1722(3):282-92
15777641
Circulation. 2004 Mar 2;109(8):966-71
14769702
J Biol Chem. 2004 Aug 6;279(32):33586-92
15173162
Biochim Biophys Acta. 2002 Jan 30;1580(1):77-93
11923102
Lipids Health Dis. 2005 Aug 12;4:16
16098225
J Lipid Res. 1992 Nov;33(11):1569-82
1464741
J Biol Chem. 1997 Apr 11;272(15):10279-86
9092579
Gastroenterology. 2006 May;130(6):1853-7
16697747
Genes Dev. 2000 Nov 15;14(22):2831-8
11090131
Biochem Biophys Res Commun. 2006 Feb 24;340(4):1259-63
16414355
Lipids Health Dis. 2010 Mar 12;9:29
20222991
Arterioscler Thromb Vasc Biol. 2001 Dec;21(12):2032-8
11742881
Science. 1997 Jul 11;277(5323):228-31
9211849
J Pharmacol Exp Ther. 2007 Feb;320(2):559-64
17135346
J Lipid Res. 2004 Feb;45(2):301-7
14657202
J Lipid Res. 2009 Aug;50(8):1653-62
19325169
Clin Ther. 2004 Nov;26(11):1758-73
15639688