Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis.
Abcb11 encodes for the liver bile salt export pump, which is rate-limiting for hepatobiliary bile salt secretion. We employed transthyretin-Abcb11 and BAC-Abcb11 transgenes to develop mice overexpressing the bile salt export pump in the liver. The mice manifest increases in bile flow and biliary secretion of bile salts, phosphatidylcholine, and cholesterol. Hepatic gene expression of cholesterol 7alpha-hydroxylase and ileal expression of the apical sodium bile salt transporter are markedly reduced, whereas gene expression of targets of the nuclear bile salt receptor FXR (ileal lipid-binding protein, short heterodimer partner (SHP) is increased. Because these changes in gene expression are associated with an increased overall hydrophobicity of the bile salt pool and a 4-fold increase of the FXR ligand taurodeoxycholate, they reflect bile salt-mediated regulation of FXR and SHP target genes. Despite the increased biliary secretion of bile salts, fecal bile salt excretion is unchanged, suggestive of an enhanced enterohepatic cycling of bile salts. Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls. We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression. Because these mice are resistant to hepatic lipid accumulation, regulation of Abcb11 may be important for the pathogenesis and treatment of steatohepatitis.
Figge
Anne
A
Department of Medicine III, University Hospital Aachen, Aachen University, 52074 Aachen, Germany.
Lammert
Frank
F
Paigen
Beverly
B
Henkel
Anne
A
Matern
Siegfried
S
Korstanje
Ron
R
Shneider
Benjamin L
BL
Chen
Frank
F
Stoltenberg
Erik
E
Spatz
Kathryn
K
Hoda
Farzana
F
Cohen
David E
DE
Green
Richard M
RM
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001647:Bile Acids and Salts; D002784:Cholesterol