Project Title: Hepatocyte-derived MIF: a key contributor to Alcoholic Liver Disease Alcoholic liver disease (ALD) is a significant cause of preventable morbidity and mortality worldwide. Alcohol- related morbidity and mortality has remained constant over the past decades, and drinking rates in developed countries continue to increase. ALD is a spectrum disorder encompassing steatosis, alcoholic hepatitis (AH), cirrhosis and even progressing to liver cancer. Therapies for ALD, and specifically AH, are unchanged for 40 years as well as ineffective for a significant proportion of ALD patients. Identifying novel biomarkers of ALD progression and the development of targeted therapies is of marked interest to public health and welfare. Macrophage Migration Inhibitory Factor (MIF), a ubiquitously expressed regulator of innate immunity with chemokine- and cytokine-like activities, is associated with ALD in humans and in ethanol feeding models in animals. MIF is increased in circulation in AH and cirrhosis patients, MIF protein expression is robustly increased in hepatocytes of AH patients, and MIF is predictive of liver morbidity and patient mortality in AH. In animal models of ethanol feeding, MIF deficiency protects from ethanol-induced liver injury and normalizes ethanol- induced inflammation and hepatocyte ER stress. Taken together, these data identified the hepatocyte as a likely tissue source and site of action for aberrant MIF expression and downstream activity in ALD.
The aim of this proposal is to test the hypothesis that that chronic, excessive alcohol increases hepatocyte MIF release that acts as a potent upstream regulator of Alcoholic Liver Disease progression through control of chemokine expression, chemokine packaging, and liver ER stress. The work proposed herein will utilize tissue-specific MIF knockouts, MIF receptor knockouts and a novel small-molecule MIF inhibitor to interrogate the role of hepatocyte-derived MIF in multiple alcohol feeding models in animals, ethanol exposure in primary hepatocyte cultures, and in human ALD patient tissues. Furthermore, the protective phenotype in MIF-deficient mice is associated with profound changes in chemokine expression in the liver and in circulating extracellular vesicles (EV). EVs are pivotal intracellular communication mediators, and the chemokine cargoes in EVs are quite dynamic in both ethanol- and MIF-dependent mechanisms. The other aim of this proposal will then transition to explore what leads to this increased hepatic MIF expression in ALD. A database search of mircoRNAs from ALD patient livers (GEO series GSE59492) revealed that a potent negative regulator of MIF expression, miR-451, is decreased along the spectrum of ALD and was selective to an alcoholic etiology of disease. The project will then expand to study EVs as a novel mechanism of therapeutic transfer in ALD, as the proposed studies will look to normalize MIF expression through restoring miR-451 expression as well as selectively inhibit MIF in the liver.

Public Health Relevance

Alcoholic liver disease is a major socioeconomic burden in the United States with limited, ineffective therapeutic interventions. This proposal will identify a key tissue source and site of action for a pivotal upstream mediator of pathophysiological liver inflammation following ethanol exposure, macrophage migration inhibitory factor. The results will provide insights to novel therapeutic interventions and diagnostic tools to combat alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Career Transition Award (K99)
Project #
1K99AA026648-01A1
Application #
9598779
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Gao, Peter
Project Start
2018-08-10
Project End
2020-07-31
Budget Start
2018-08-10
Budget End
2019-07-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195