Transgenic overexpression of Abcb11 enhances biliary bile salt outputs, but does not affect cholesterol cholelithogenesis in mice.
BACKGROUND
Cholesterol gallstone disease is a complex genetic trait and induced by multiple but as yet unknown genes. A major Lith gene, Lith1 was first identified on chromosome 2 in gallstone-susceptible C57L mice compared with resistant AKR mice. Abcb11, encoding the canalicular bile salt export pump in the hepatocyte, co-localizes with the Lith1 QTL region and its hepatic expression is significantly higher in C57L mice than in AKR mice.


METHODS
To investigate whether Abcb11 influences cholesterol gallstone formation, we created an Abcb11 transgenic strain on the AKR genetic background and fed these mice with a lithogenic diet for 56 days.


RESULTS
We excluded functionally relevant polymorphisms of the Abcb11 gene and its promoter region between C57L and AKR mice. Overexpression of Abcb11 significantly promoted biliary bile salt secretion and increased circulating bile salt pool size and bile salt-dependent bile flow rate. However, biliary cholesterol and phospholipid secretion, as well as gallbladder size and contractility were comparable in transgenic and wild-type mice. At 56 days on the lithogenic diet, cholesterol saturation indexes of gallbladder biles and gallstone prevalence rates were essentially similar in these two groups of mice.


CONCLUSIONS
Overexpression of Abcb11 augments biliary bile salt secretion, but does not affect cholelithogenesis in mice.
Wang
Helen H
HH
Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA 02215, USA.
Lammert
Frank
F
Schmitz
Anne
A
Wang
David Q-H
DQ
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002769:Cholelithiasis / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D005704:Gallbladder / Q000503:physiopathology; D042882:Gallstones / Q000235:genetics*; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary
Gastroenterology. 2001 Jan;120(1):221-38
11208732
Nat Genet. 2005 Aug;37(8):835-43
15995705
Cell. 1993 Nov 5;75(3):451-62
8106172
Biochim Biophys Acta. 2005 Mar 21;1733(1):90-9
15749059
J Clin Invest. 1995 Jan;95(1):31-8
7814632
Gastroenterology. 2001 May;120(6):1459-67
11313316
Biochim Biophys Acta. 2001 Apr 16;1518(3):271-5
11311939
J Lipid Res. 2002 Jul;43(7):1105-13
12091495
J Biol Chem. 2004 Jan 23;279(4):2790-9
14570929
Physiol Genomics. 2000 Nov 09;4(1):59-65
11074014
Lipids. 2009 Jun;44(6):521-6
19408031
J Lipid Res. 2009 Apr;50 Suppl:S406-11
19017613
Nat Genet. 1998 Nov;20(3):233-8
9806540
J Lipid Res. 1978 Nov;19(8):945-55
731129
Hepatology. 2005 Oct;42(4):894-904
16175613
Am J Physiol Gastrointest Liver Physiol. 2005 Nov;289(5):G831-41
15860642
Gastroenterology. 2006 Dec;131(6):1943-70
17087948
Mamm Genome. 2005 Dec;16(12):903-8
16341669
J Lipid Res. 1987 May;28(5):589-95
3598401
J Lipid Res. 1999 Nov;40(11):2066-79
10553010
J Biol Chem. 1998 Apr 17;273(16):10046-50
9545351
Gene. 2000 Jan 4;241(1):117-23
10607905
Nat Genet. 2001 Jan;27(1):79-83
11138003
J Biol Chem. 1992 Oct 5;267(28):20248-54
1356977
J Lipid Res. 2001 Nov;42(11):1820-30
11714851
J Lipid Res. 1997 Jul;38(7):1395-411
9254065
Genes Dev. 2003 Jul 1;17(13):1581-91
12815072
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7729-33
7644485
J Lipid Res. 1999 Nov;40(11):2080-90
10553011
J Clin Invest. 2002 Sep;110(5):671-80
12208868
Curr Gastroenterol Rep. 2004 Apr;6(2):140-50
15191694
Hepatology. 2010 Jan;51(1):277-85
19957370
Science. 2000 Dec 1;290(5497):1771-5
11099417
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2011-6
11172067
J Lipid Res. 1989 May;30(5):719-30
2760545
J Biol Chem. 1959 Mar;234(3):466-8
13641241
Gastroenterology. 2003 Aug;125(2):452-9
12891548
Nat Genet. 1997 Nov;17(3):280-4
9354790
Lancet. 2006 Jul 15;368(9531):230-9
16844493
Hepatology. 2007 Sep;46(3):793-801
17626266
Hepatology. 2004 Jan;39(1):117-28
14752830
Gastroenterology. 2003 Sep;125(3):868-81
12949731
Hepatology. 2006 Sep;44(3):650-7
16941683
J Lipid Res. 1996 Mar;37(3):606-30
8728323
J Lipid Res. 2003 May;44(5):1042-59
12588946
Gastroenterology. 2006 Jul;131(1):210-22
16831603
Nat Genet. 2007 Aug;39(8):995-9
17632509
J Lipid Res. 2004 Dec;45(12):2185-98
15375181