Alcoholic hepatitis 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 hepatitis result from the gut-to-liver interaction. Vitamin D deficiency is highly prevalent in patients with alcoholic hepatitis. VitaminD supplementation regulates the expression of tight junction proteins, enhances antimicrobial defenses and reduces proinflammatory cytokines in the gut. Vitamin D targets osteopontin via a vitamin D-responsive element in the osteopontin promoter. Milk osteopontin protects the gut by maintaining the epithelial barrier function, providing mucosal defense, preventing sepsis and the inflammatory response. So far, a link between vitamin D and osteopontin in protecting from alcoholic hepatitis has not been established. We believe that nutritional therapy using vitamin D and milk osteopontin could protect from alcohol-induced liver injury. In this Application we will focus on testing the Central Hypothesis """"""""Dietary supplementation with vitamin D or milk osteopontin could prevent alcoholic hepatitis due to the gut protective and antisteatotic actions of osteopontin"""""""". In particular, we hypothesize that vitamin D and 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. We will develop new in vivo models of alcoholic hepatitis to further our understanding of the mechanisms of liver injury. Using these models, mice will be treated with vitamin D or milk osteopontin to assess their therapeutic potential. To prove our hypothesis we plan three Specific Aims.
In Aim 1, we will analyze if vitamin D and milk osteopontin block 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 vitamin D and milk osteopontin blunt steatosis by targeting fatty acid metabolism;and second, we will dissect if the ability of osteopontin to bind lipopolysaccharide lowers Kupffer cell activation, TNF? production as well as other pro-inflammatory cytokines. The chronic Lieber-DeCarli model along with dextran sodium sulfate or lipopolysaccharide treatment will be used.
In Aim 3, a new model of alcoholic hepatitis based on autophagy blockade will be developed. Next, we will identify if vitamin D and milk osteopontin reduce steatosis by activating the autophagy pathway independent of targeting bacterial translocation or binding lipopolysaccharide. Thus, the Overall Goal of this Application is to investigate whether dietary administration of vitamin D and milk osteopontin could be an efficient low-cost therapeutic strategy for slowing down or preventing the progression of alcoholic hepatitis.

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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1)
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Wang, Joe
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Ge, Xiaodong; Arriazu, Elena; Magdaleno, Fernando et al. (2018) High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice. Hepatology 68:2380-2404
Magdaleno, Fernando; Ge, Xiaodong; Fey, Holger et al. (2018) Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease. Hepatol Commun 2:84-98
Magdaleno, Fernando; Blajszczak, Chuck C; Nieto, Natalia (2017) Key Events Participating in the Pathogenesis of  Alcoholic Liver Disease. Biomolecules 7:
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
Magdaleno, Fernando; Arriazu, Elena; Ruiz de Galarreta, Marina et al. (2016) Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis. J Hepatol 65:963-971
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

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