Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice

Yan Xie, Ho Yee Joyce Fung, Elizabeth P. Newberry, Susan Kennedy, Jianyang Luo, Rosanne M. Crooke, Mark J. Graham, Nicholas O. Davidson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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 LDfed 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.

Original languageEnglish
Pages (from-to)540-548
Number of pages9
JournalJournal of lipid research
Volume55
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • ATP binding cassette transporter
  • Bile acid
  • Canalicular cholesterol
  • Hepatic cholesterol metabolism
  • Phospholipid

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