Although apoptosis has been associated with the progression of alcohol-induced liver injury, no direct evidence demonstrates that inhibition of apoptosis actually prevents alcoholic liver damage. We found that inhibition of apoptosis did not, in fact, attenuate ethanol-induced hepatocyte injury, expression of pro- inflammatory cytokines/chemokines or oxidative stress in Bid-deficient mice. Recently, a newly described mode of cell death, called necroptosis, has been implicated in caspase-independent cell injury in a variety of cell types. Necroptosis is activated in a fashion similar to apoptosis, but morphologically, the process resembles necrosis. Signaling mechanisms involving receptor-interacting protein kinases (RIP), including RIP1 and RIP3, mediate necroptosis induced by the activation of death ligands, including TNFa or Fas. In preliminary studies, we find, for the first time, that expression of RIP3, a central mediator of necroptosis, is increased in mouse livers following chronic ethanol feeding in parallel to the markers of hepatocyte injury. RIP3 is also induced in mouse liver in other models of hepatic injury including carbon tetrachloride (CCl4)- and ischemia/reperfusion-induced liver damage. Moreover, in pilot experiments we now show that RIP3-deficient mouse are protected from ethanol-induced liver injury and inflammation. Here we hypothesize that hepatocyte injury following chronic ethanol feeding is regulated by RIP3-driven caspase-independent cell death. To test our hypothesis, we will use mice deficient in RIP3 as well as treatment with necrostatin-1, a necroptosis inhibitor, during ethanol feeding. We will also use mice deficient in CYP2E1, TNFR1, and TLR4 to determine upstream activators of the RIP3-signaling pathway in response to ethanol feeding. This study will explore new pathways of cell death in mouse liver following ethanol feeding. The proposed work will help us to determine new molecular targets for better therapeutic management of alcoholic liver disease (ALD).

Public Health Relevance

Excessive alcohol consumption leads to liver damage. There is no straightforward treatment available to date. Liver transplantation is the only possible optio for the patient suffering from alcohol-induced liver damage. Our proposed work will help us to better understand the cause of alcoholic liver damage as well as identify new therapeutic targets for prevention of alcoholic liver damage.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Biomedical Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Zhou, Hao; Yu, Minja; Roychowdhury, Sanjoy et al. (2017) Myeloid-MyD88 Contributes to Ethanol-Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation. Alcohol Clin Exp Res 41:719-726
Roychowdhury, Sanjoy; McCullough, Rebecca L; Sanz-Garcia, Carlos et al. (2016) Receptor interacting protein 3 protects mice from high-fat diet-induced liver injury. Hepatology 64:1518-1533
Smathers, Rebecca L; Chiang, Dian J; McMullen, Megan R et al. (2016) Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice. Mol Immunol 72:9-18
Luo, Xiao-Juan; Yang, Hong-Ye; Niu, Li-Na et al. (2016) Translation of a solution-based biomineralization concept into a carrier-based delivery system via the use of expanded-pore mesoporous silica. Acta Biomater 31:378-387
McCullough, Rebecca L; McMullen, Megan R; Das, Dola et al. (2016) Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 75:122-32
Barnes, Mark A; Roychowdhury, Sanjoy; Nagy, Laura E (2014) Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1. Redox Biol 2:929-35
Bakhautdin, Bakytzhan; Das, Dola; Mandal, Palash et al. (2014) Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J Hepatol 61:1029-37
Roychowdhury, Sanjoy; Chiang, Dian J; McMullen, Megan R et al. (2014) Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1? Pharmacol Res Perspect 2:e00061