Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice.
Previous studies demonstrated that L-Fabp KO mice are more susceptible to lithogenic diet (LD)-induced gallstones because of altered hepatic cholesterol metabolism and increased canalicular cholesterol secretion. Other studies demonstrated that liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) reduced LD-induced gallstone formation by increasing biliary phospholipid secretion. Here we show that mice with combined deletion (i.e., DKO mice) are protected from LD-induced gallstone formation. Following 2 weeks of LD feeding, 73% of WT and 100% of L-Fabp KO mice developed gallstones versus 18% of Mttp-LKO and 23% of DKO mice. This phenotype was recapitulated in both WT and L-Fabp KO mice treated with an Mttp antisense oligonucleotide (M-ASO). Biliary cholesterol secretion was increased in LD-fed L-Fabp KO mice and decreased in DKO mice. However, phospholipid secretion was unchanged in LD-fed Mttp-LKO and DKO mice as well as in M-ASO-treated mice. Expression of the canalicular export pump ABCG5/G8 was reduced in LD-fed DKO mice and in M-ASO-treated L-Fabp KO mice. We conclude that liver-specific Mttp deletion not only eliminates apical lipoprotein secretion from hepatocytes but also attenuates canalicular cholesterol secretion, which in turn decreases LD-induced gallstone susceptibility.
Department of Medicine, Washington University School of Medicine, St. Louis, MO; and.
Yan
Y
Xie
Ho Yee Joyce
HY
Fung
Elizabeth P
EP
Newberry
Susan
S
Kennedy
Jianyang
J
Luo
Rosanne M
RM
Crooke
Mark J
MJ
Graham
Nicholas O
NO
Davidson
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D050556:Fatty Acid-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D042882:Gallstones / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000209:etiology / Q000235:genetics; D015151:Immunoblotting; D008055:Lipids / Q000032:analysis / Q000097:blood; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008055:Lipids; D008074:Lipoproteins; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol
ATP binding cassette transporter; bile acid; canalicular cholesterol; hepatic cholesterol metabolism; phospholipid