Alcoholic liver disease is a common cause for morbidity and mortality in the U.S. Alcoholic steatohepatitis, the early phase of the disease, is reversible and understanding its molecular pathogenesis is essential to identify new therapeutic targets for this disease. The Wnt/beta-catenin pathway is an intracellular signaling pathway that plays an important role in normal liver development, growth, and regeneration. The main aim of this proposal is to understand the role of this pathway in the molecular pathogenesis of alcohol-induced steatohepatitis using mouse models of alcoholic liver disease. The central hypothesis being tested is that the protein beta-catenin, a key player in the Wnt signaling pathway, plays a protective role in the development of alcoholic steatohepatitis. To test this hypothesis, in Specific Aim 1, the effects of ethanol on Wnt/beta-catenin signaling will be determined both in vitro and in vivo. Ethanol-treated primary hepatocyte cultures, Kupffer cell cultures, and hepatoma cell lines will be used to investigate changes in Wnt signaling in vitro. Ethanol- fed mice will be utilized to study changes in Wnt signaling in vivo.
In Specific Aim 2, the effects of loss of b- catenin on the liver with chronic ethanol feeding will be determined using liver-specific b-catenin knockout mice. Liver histology, markers of liver injury, oxidative stress, hepatic fibrosis, cytokine profile, and alterations in the expression of metabolic genes will be characterized in the livers of ethanol-fed knockout mice.
In Specific Aim 3, the effect of ethanol feeding on the liver in transgenic mice expressing a stable, mutated-form of b-catenin in the liver will be investigated. These studies will provide new insights into the molecular events underlying development of alcoholic steatohepatitis. This proposal is for a five-year Mentored Career Development Award and the studies will be carried out under the primary mentorship of Dr.Satdarshan Monga at the University of Pittsburgh. The project will provide an outstanding opportunity to the principal investigator, Dr. Behari, to develop into an independent investigator in the area of alcohol-related liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AA017622-05
Application #
8321620
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2008-09-20
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$207,045
Indirect Cost
$15,337
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit et al. (2014) Stratification of risk of death in severe acute alcoholic hepatitis using a panel of adipokines and cytokines. Alcohol Clin Exp Res 38:2712-21
Liu, Shiguang; Yeh, Tzu-Hsuan; Singh, Vijay P et al. (2012) ýý-catenin is essential for ethanol metabolism and protection against alcohol-mediated liver steatosis in mice. Hepatology 55:931-40
Behari, Jaideep; Yeh, Tzu-Hsuan; Krauland, Lindsay et al. (2010) Liver-specific beta-catenin knockout mice exhibit defective bile acid and cholesterol homeostasis and increased susceptibility to diet-induced steatohepatitis. Am J Pathol 176:744-53
Behari, Jaideep; Chalasani, Naga (2010) Challenging the rodent hegemony: a new rabbit model of nonalcoholic steatohepatitis. Am J Pathol 177:10-2
Yeh, Tzu-Hsuan; Krauland, Lindsay; Singh, Vijay et al. (2010) Liver-specific ?-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis. Hepatology 52:1410-9
Behari, Jaideep (2010) The Wnt/?-catenin signaling pathway in liver biology and disease. Expert Rev Gastroenterol Hepatol 4:745-56