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Date of Award

Spring 3-26-2012

Author's School

College of Arts & Sciences

Author's Department/Program

Biology

Abstract

Cholesterol gallstone disease (GS) is a common affliction that is linked to the imbalance of biliary lipid content, including cholesterol (CH), phospholipids (PL) and bile acids (BA), which results in the precipitation of cholesterol crystals. This study is aimed at examining the role of liver fatty acid binding protein (L-Fabp) and hepatic microsomal triglyceride transfer protein (Mttp) as genetic modifiers of the gallstone susceptibility trait.

L-Fabp plays a key role as a cytosolic cholesterol sensor and regulates hepatic fatty acid and CH metabolism. Mttp is a dominant regulator of lipoprotein assembly and secretion from hepatocytes into the plasma compartment, but its role in biliary canalicular lipid secretion remains unknown. Our earlier studies showed that L-Fabp–/– mice exhibited increased susceptibility to diet induced GS through increased biliary CH secretion. Other studies demonstrated that liver specific Mttp deletion (Mttp-LKO) prevented diet-induced GS by increasing biliary PL secretion. My studies explored the hypothesis that hepatic Mttp deletion in the L-Fabp null background would abrogate diet induced GS formation. Accordingly, we used two strategies to generate mice with deficient hepatic Mttp in the L-Fabp–/– background. First, we used conditional genetic Mttp deletion (L-MttpLKO) and secondly we used antisense mediated Mttp knockdown (L-MttpASO) both of which led to attenuated expression of Mttp. We fed all groups of mice with a lithogenic diet for 2 weeks and evaluated GS incidence, serum and hepatic lipid content, biliary lipid secretions and mRNA expression of genes related to hepatic lipid transporters and lipogenic genes.

After LD feeding for two weeks, L-MttpLKO and L-MttpASO mice were both protected against GS formation when compared to their control mice respectively. There was decreased biliary CH secretion in L-MttpLKO mice. L-MttpASO mice exhibited a trend to decreased canalicular CH secretion with a significant decrease in the expression of the cholesterol transporters. These data suggest that ablation of hepatic Mttp protects L-Fabp–/– mice from diet-induced GS formation by reducing canalicular CH secretion and implies that Mttp plays a dominant role in pathways regulating canalicular CH secretion.

Language

English (en)

Advisor/Committee Chair

Nicholas Davidson

Advisor/Committee Chair's Department

Washington University School of Medicine in St. Louis, Gastroenterology Department