Inhibition of intestinal bile acid absorption has been shown to reduce plasma cholesterol. Although, bile acid sequestrants are clinically proven to lower cholesterol, poor patient compliance necessitates the development of better therapeutic modalities to directly inhibit bile acid absorption. Apical Sodium Dependent Bile Acid Transporter (ASBT) absorbs majority of the bile acids in the ileum and is essential for maintaining bile acid pool in the enterohepatic circulation. Therefore, ASBT inhibition represents an attractive therapeutic means for lowering plasma cholesterol. In this regard, recent studies from our laboratory demonstrated that ASBT is inhibited by signaling intermediates including protein tyrosine phosphatases (PTPases) via membrane recycling events. Also beneficial dietary components such as green tea catechin, (-)-epigallocatechin-3-gallate, EGCG, inhibits ASBT function in a lipid-raft dependent manner. We hypothesized that phosphorylation/dephosphorylation processes, lipid raft-dependent mechanisms and membrane trafficking events play critical roles in the inhibition of ASBT function. Hence, a comprehensive understanding of these inhibitory pathways is crucial to exploit their utilization as an effective therapy for hypercholesterolemia associated with diabetes mellitus. Our preliminary studies showed that ASBT function and expression are upregulated in rat model of streptozotocin (STZ)-induced diabetes mellitus. This in vivo model of diabetes mellitus will provide an exceptional tool to investigate the underlying mechanisms of ASBT upregulation in diabetes mellitus as well as determining the impact of ASBT inhibition on associated hypercholesterolemia. Our studies are designed to systematically delineate the cellular and molecular mechanisms inhibiting ASBT utilizing in vitro models and to examine their dysregulation in vivo utilizing diabetes mellitus rat model.
In Specific Aim 1, we will investigate the regulation of ASBT function and phosphorylation by protein phosphatases (PPase) in cell culture models.
In Specific Aim 2, our studies will focus on elucidating the inhibitory mechanisms of ASBT function by membrane recycling events and lipid rafts as well as delineating the molecular basis for EGCG-mediated inhibition. Studies designed for Specific Aim 3 will focus on investigating mechanisms underlying ASBT upregulation in rat model of STZ-induced diabetes mellitus and determine the efficacy of the beneficial dietary compound EGCG and specific ASBT inhibitors (developed by Biotechnology Company Albireo) in lowering the levels of plasma cholesterol. Our proposed studies are critical for providing novel insights into the regulation of ASBT under normal and pathophysiological conditions and may provide better strategies for the management of hypercholesterolemia associated with several disorders.

Public Health Relevance

An increase in intestinal bile acid absorption has been implicated in the elevated plasma cholesterol levels and the increased risk of cardiovascular disorders in patients with diabetes mellitus. The major protein responsible for bile acid absorption is ileal ASBT. Therefore, investigating the mechanisms of ASBT inhibition is crucial to improve current therapy of hypercholesterolemia especially in diabetic patients, who do not efficiently respond to available therapeutic modalities. The proposed studies will focus on elucidating the mechanisms involved in the inhibition of ASBT function and evaluating their impact on hypercholesterolemia in rat model of diabetes mellitus. These studies have direct relevance to public health because of the high incidence of diabetes mellitus, and are of a great importance for designing better therapeutic modalities for the management of cholesterol-related disorders in the future.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Sherker, Averell H
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University of Illinois at Chicago
Internal Medicine/Medicine
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United States
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Jayawardena, Dulari; Guzman, Grace; Gill, Ravinder K et al. (2017) Expression and localization of VPAC1, the major receptor of vasoactive intestinal peptide along the length of the intestine. Am J Physiol Gastrointest Liver Physiol 313:G16-G25
Anabazhagan, Arivarasu N; Chatterjee, Ishita; Priyamvada, Shubha et al. (2017) Methods to Study Epithelial Transport Protein Function and Expression in Native Intestine and Caco-2 Cells Grown in 3D. J Vis Exp :
Chatterjee, Ishita; Kumar, Anoop; Castilla-Madrigal, Rosa MarĂ­a et al. (2017) CDX2 upregulates SLC26A3 gene expression in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 313:G256-G264
Singhal, Megha; Manzella, Christopher; Soni, Vinay et al. (2017) Role of SHP2 protein tyrosine phosphatase in SERT inhibition by enteropathogenic E. coli (EPEC). Am J Physiol Gastrointest Liver Physiol 312:G443-G449
Malhotra, Pooja; Aloman, Costica; Ankireddy, Aparna et al. (2017) Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 313:G376-G385
Kumar, Anoop; Chatterjee, Ishita; Gujral, Tarunmeet et al. (2017) Activation of Nuclear Factor-?B by Tumor Necrosis Factor in Intestinal Epithelial Cells and Mouse Intestinal Epithelia Reduces Expression of the Chloride Transporter SLC26A3. Gastroenterology 153:1338-1350.e3
Priyamvada, Shubha; Anbazhagan, Arivarasu N; Kumar, Anoop et al. (2016) Lactobacillus acidophilus stimulates intestinal P-glycoprotein expression via a c-Fos/c-Jun-dependent mechanism in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 310:G599-608
Anbazhagan, Arivarasu N; Priyamvada, Shubha; Gujral, Tarunmeet et al. (2016) A novel anti-inflammatory role of GPR120 in intestinal epithelial cells. Am J Physiol Cell Physiol 310:C612-21
Kumar, Anoop; Anbazhagan, Arivarasu N; Coffing, Hayley et al. (2016) Lactobacillus acidophilus counteracts inhibition of NHE3 and DRA expression and alleviates diarrheal phenotype in mice infected with Citrobacter rodentium. Am J Physiol Gastrointest Liver Physiol 311:G817-G826
Ticho, Alexander L; Alrefai, Waddah A (2016) Chronic ethanol exposure closes the door to vitamin C in pancreatic acinar cells. Focus on ""Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure"". Am J Physiol Cell Physiol 311:C127-8

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