Abstract

Bile salt secretion is the major driving force for bile formation. Bile salts are amphipathic molecules that solubilize lipids and hydrophobic nutrients prior to gut absorption, enhance hepatobiliary secretion, prevent cholesterol gallstone formation and transcriptionally regulate many hepatic and intestinal genes involved in lipid metabolism. The rate-limiting step for hepatocellular bile salt transport is ATP-dependent canalicular secretion, and Abcb11 (BSEP) is the gene that encodes for this transporter. In humans, the inter-individual variability of Abcb11 is large. However, the in vivo effects of Abcb11 in both normal physiology and pathophysiologic states remain poorly understood. The Principal Investigator has recently developed transgenic transthyretin promoter-Abcbl 1 (TTR-Abcb11) mice that functionally over-express Abcb11 in the liver canalicular membrane. This mouse can allow one to perform novel in vivo investigations into the physiologic role of Abcbl 1. Thus, the Specific Aims of the proposal are:
Specific Aim 1 : To determine the mechanism(s) by which Abcb11 regulates gene expression in the liver and enterohepatic circulation, with the resultant effects on hepatobiliary and systemic lipid metabolism.
Specific Aim 2 : To define the mechanism(s) with which Abcb11 induces: fatty liver diseases and cholelithiasis, by feeding TTR-Abcb11 mice well-characterized murine diets that are nutritional models of these diseases.
Specific Aim 3 : To determine mechanisms by which hepatic Abcb11 regulates systemic lipid metabolism, hyperlipidemia and atherosclerosis by employing """"""""classic"""""""" murine models of hypercholesterolemia. This proposal utilizes state-of-the-art mouse genetics, molecular biology and lipid biochemical techniques to examine the molecular mechanisms responsible for diseases including fatty liver, cholelithiasis and systemic lipid disorders. These studies will further our understanding of Abcbl 1 function on hepatic bile salt transport as well as hepatobiliary and systemic lipid metabolism. These data are critical for the development of rational therapies for common systemic disorders of lipid metabolism and diseases of the gallbladder and liver. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059580-08
Application #
7418700
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2000-09-30
Project End
2009-10-30
Budget Start
2008-05-01
Budget End
2009-10-30
Support Year
8
Fiscal Year
2008
Total Cost
$251,456
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Liu, Xiaoying; Guo, Grace L; Kong, Bo et al. (2018) Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice. Hepatology 68:304-316
Koppe, Sean W P; Elias, Marc; Moseley, Richard H et al. (2009) Trans fat feeding results in higher serum alanine aminotransferase and increased insulin resistance compared with a standard murine high-fat diet. Am J Physiol Gastrointest Liver Physiol 297:G378-84
Rinella, Mary E; Elias, Marc S; Smolak, Robin R et al. (2008) Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 49:1068-76
Johnson, Laura E; Elias, Marc S; Bolick, David T et al. (2008) The G protein-coupled receptor G2A: involvement in hepatic lipid metabolism and gallstone formation in mice. Hepatology 48:1138-48
Emerick, Karan M; Elias, Marc S; Melin-Aldana, Hector et al. (2008) Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion. BMC Gastroenterol 8:47
Rangnekar, Amol S; Lammert, Frank; Igolnikov, Alexander et al. (2006) Quantitative trait loci analysis of mice administered the methionine-choline deficient dietary model of experimental steatohepatitis. Liver Int 26:1000-5
Henkel, Anne; Wei, Zhixin; Cohen, David E et al. (2005) Mice overexpressing hepatic Abcb11 rapidly develop cholesterol gallstones. Mamm Genome 16:903-8
Sundaram, Shikha S; Whitington, Peter F; Green, Richard M (2005) Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet. Am J Physiol Gastrointest Liver Physiol 288:G1321-7
Figge, Anne; Lammert, Frank; Paigen, Beverly et al. (2004) Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis. J Biol Chem 279:2790-9
Sahai, Atul; Malladi, Padmini; Melin-Aldana, Hector et al. (2004) Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol 287:G264-73

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