Alcoholic liver disease is a leading cause of liver disease and death worldwide;thus, there is an urgent need to develop novel therapeutic interventions. Key events for the onset and progression of alcoholic liver disease result from the gut-to-liver interaction. Milk osteopontin protects the gut by maintaining the epithelial barrier function, providing mucosal defense, preventing sepsis and the inflammatory response. So far, a role for milk osteopontin in protecting from alcoholic liver disease has not been established. We believe that nutritional therapy using milk osteopontin could protect from alcohol-induced liver injury. In this Application we will focus on testing the Central Hypothesis """"""""Dietary supplementation with milk osteopontin could prevent alcoholic liver disease due to its gut protective and antisteatotic actions"""""""". In particular, we hypothesize that milk osteopontin will: 1) Target the gut-liver axis protecting the intestinal mucosal barrier and blocking the translocation of Gram-negative bacteria from the gut into the portal circulation thus lowering lipopolysaccharide levels;2) Prevent steatosis and liver injury by targeting fatty acid metabolism and decreasing lipopolysaccharide-mediated Kupffer cell activation and TNF? production;and 3) Avert hepatic steatosis, inflammation and liver injury by increasing autophagy, a recently identified pathway regulating steatosis. Using models of alcohol-induced liver injury, mice will be treated with milk osteopontin to assess its therapeutic potential. To prove our hypothesis we plan three Specific Aims.
In Aim 1, we will analyze if milk osteopontin blocks the ethanol-mediated increase in gut permeability, bacterial translocation and lipopolysaccharide availability. The chronic Lieber-DeCarli model along with dextran sodium sulfate treatment will be used.
In Aim 2, first, we will determine whether milk osteopontin blunts steatosis by targeting fatty acid metabolism;and second, we will dissect if the ability of milk osteopontin to bind lipopolysaccharide lowers Kupffer cell activation, TNF? production as well as other pro-inflammatory cytokines and oxidative/nitrosative stress. The chronic Lieber-DeCarli model along with dextran sodium sulfate or lipopolysaccharide treatment will be used.
In Aim 3, a new model of alcoholic liver disease based on autophagy blockade will be developed. Next, we will identify if milk osteopontin reduces steatosis and liver injury by activating the autophagy pathway independent of targeting bacterial translocation or binding lipopolysaccharide. Thus, the Overall Goal of this Proposal is to investigate whether dietary administration of milk osteopontin could be an efficient low-cost therapeutic strategy for slowing down or preventing the progression of alcoholic liver disease.

Public Health Relevance

Alcoholic liver disease affects several million people worldwide and progresses to alcoholic steatohepatitis, fibrosis and cirrhosis in many patients. We have recently identified osteopontin as a vitamin D-inducible protein with the ability to protect from alcohol-induced liver injury. The work proposed herein will evaluate and elucidate the mechanisms by which the protective effects of vitamin D and osteopontin occur;thus, contributing to design new, accessible and inexpensive therapies to prevent or slow down alcoholic hepatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AA021887-01
Application #
8428356
Study Section
Special Emphasis Panel (ZAA1-JJ (07))
Program Officer
Wang, Joe
Project Start
2012-09-25
Project End
2017-06-30
Budget Start
2012-09-25
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$406,800
Indirect Cost
$166,800
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Arriazu, Elena; Ge, Xiaodong; Leung, Tung-Ming et al. (2017) Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 66:1123-1137
Lu, Yongke; Ward, Stephen C; Nieto, Natalia (2014) Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury is attenuated in mice with partial ablation of argininosuccinate synthase. Alcohol Clin Exp Res 38:649-56
Ge, Xiaodong; Antoine, Daniel J; Lu, Yongke et al. (2014) High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD). J Biol Chem 289:22672-91
Ge, Xiaodong; Leung, Tung-Ming; Arriazu, Elena et al. (2014) Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-? and prevents early alcohol-induced liver injury in mice. Hepatology 59:1600-16
Arriazu, Elena; Ruiz de Galarreta, Marina; Cubero, Francisco Javier et al. (2014) Extracellular matrix and liver disease. Antioxid Redox Signal 21:1078-97
Wang, Xiaodong; Lopategi, Aritz; Ge, Xiaodong et al. (2014) Osteopontin induces ductular reaction contributing to liver fibrosis. Gut 63:1805-18
Ge, Xiaodong; Lu, Yongke; Leung, Tung-Ming et al. (2013) Milk osteopontin, a nutritional approach to prevent alcohol-induced liver injury. Am J Physiol Gastrointest Liver Physiol 304:G929-39
Leung, Tung-Ming; Wang, Xiaodong; Kitamura, Naoto et al. (2013) Osteopontin delays resolution of liver fibrosis. Lab Invest 93:1082-9