Cholestatic liver diseases are highly prevalent causes of progressive liver disease in the United States and are a common indication for liver transplantation. Unfortunately, current medical therapies are not curative and may not prevent disease progression. Over the past decade, the Unfolded Protein Response (UPR), an adaptive cellular response to Endoplasmic Reticulum (ER) stress, has been implicated in the pathogenesis of many liver diseases. The role of the UPR in hepatic bile salt toxicity and cholestatic liver disease, however, remains unexplored. X-box binding protein 1-spliced (XBP1s) is a key regulatory molecule of the UPR that our preliminary data indicates is protective from bile salt injury. The central hypothesis of this proposal is that XBP1s is protective to the live during cholestasis~ and attenuated hepatic expression of XBP1s results in diminished expression of liver bile salt transporters and increased susceptibility to hepatic bile salt liver injury. Thus, in this proposal we will feed diets supplemented with cholic acid to mice and define the role of XBP1s and downstream targets in hepatic bile salt injury (Specific Aim #1). CYP7a1 is the rate-limiting step in bile salt synthesis, and inhibition of CYP7a1 expression and activity can act as a negative feedback mechanism to reduce the bile salt pool. We present preliminary data indicating that activation of the hepatic UPR markedly reduces expression of hepatic CYP7a1, likely via a XBP1s- mediated pathway. Thus, we will determine that the Unfolded Protein Response and XBP1s suppress hepatic Cyp7a1 expression, function and bile salt synthesis (Specific Aim #2). Finally, in order to directly determine that attenuation of hepatic XBP1s expression increases susceptibility to bile salt hepatotoxicity, we will develop genetically-modified mice with a liver-specific deletion of XBP1. We will develop liver-specific XBP1(-/-) mice in order to confirm the protective role, and define the protective mechanisms, of XBP1s in liver bile salt injury (Specific Aim #3). While this proposal focuses on hepatic XBP1s, the long-term goal is to develop a line of research to identify UPR signaling pathways that can serve as therapeutic targets for the treatment of cholestatic liver diseases. This proposal utilizes state-of-the-art mouse genetics, molecular biology and lipid biochemical techniques to further our understanding of the protective role of XBP1s in bile salt injury and cholestasis. Investigations identifying the role of the XBP1s signaling pathway and its effects on bile salt-induced liver injury may identify a novel pathway and potential targets for drug development to treat cholestatic liver diseases.

Public Health Relevance

Cholestatic liver diseases are common causes of progressive liver disease that can lead to cirrhosis and hepatic failure. Unfortunately, there are few medical therapies for cholestatic liver diseases. We will study role of bile salts in liver injury, and the mechanisms and protective effects of a liver protein named XBP1s in preventing hepatic bile salt injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093807-02
Application #
8551664
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2012-09-26
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$324,277
Indirect Cost
$114,389
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
Pasricha, Sarina; Kenney-Hunt, Jane; Anderson, Kristy et al. (2015) Identification of eQTLs for hepatic Xbp1s and Socs3 gene expression in mice fed a high-fat, high-caloric diet. G3 (Bethesda) 5:487-96
Liu, Xiaoying; Henkel, Anne S; LeCuyer, Brian E et al. (2015) Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet. Am J Physiol Gastrointest Liver Physiol 309:G965-74
Olivares, Shantel; Green, Richard M; Henkel, Anne S (2014) Endoplasmic reticulum stress activates the hepatic activator protein 1 complex via mitogen activated protein kinase-dependent signaling pathways. PLoS One 9:e103828
Henkel, Anne; Green, Richard M (2013) The unfolded protein response in fatty liver disease. Semin Liver Dis 33:321-9
Henkel, Anne S; Gooijert, Karin E R; Havinga, Rick et al. (2013) Hepatic overexpression of Abcb11 in mice promotes the conservation of bile acids within the enterohepatic circulation. Am J Physiol Gastrointest Liver Physiol 304:G221-6