Alcohol-induced liver disease (ALD) due to chronic alcohol abuse remains one of the most common and deadly chronic liver diseases, throughout the world. Not all alcoholics develop end-stage ALD (cirrhosis), for which liver transplantation is the only life-saving alternative. Unfortunately, ALD may remain undetected in early stages of progression due to lack of precise diagnostic markers including liver enzymes, which may not be conclusive in some cases. Therefore, it is critical to identify serum factors that can indicate hepatic abnormality without invasive and painful liver biopsy. Our work using a mouse model of hepatic deficiency of a protein named augmenter of liver regeneration (ALR) indicates that the defects in ALR gene and serum ALR levels could be reliable diagnostic indicators of the susceptibility of humans to develop end-stage ALD. ALR is produced and secreted constitutively by hepatocytes. Very high (>90%) homology between the mRNA and protein sequences of mouse and human ALR suggests that the experimental findings related to ALR in mouse have direct relevance to human pathophysiology. Our recently developed novel liver-specific conditional ALR- knockout mouse demonstrates several features of ALD. The heterozygous (ALR) mice that exhibit normal liver structure and function develop very heavy steatosis, hepatic inflammation and fibrosis upon alcohol ingestion for 4 weeks, in contrast to pair-matched wild type mice that develop only mild form of steatosis. The serum ALR also is much lower in ALR mice than the WT mice. We also found reduced hepatic ALR levels in humans with advanced ALD, and at least 24 different polymorphisms in the human ALR gene. Whether any of these polymorphisms are related to ALR deficiency and ALD remains unknown. Based on these strong lines of evidence, we hypothesize that the adult ALR mice will develop ALD similar to human ALD (including hepatic fibrosis). We further hypothesize that some of the polymorphisms in the ALR gene are responsible for susceptibility of the humans to develop advanced ALD.
Our Specific Aims are:
Aim 1 : To characterize accelerated and augmented alcohol-induced liver disease in ALR mice.
Aim 2 : To determine whether common genetic polymorphism or rare genetic variation in ALR predispose individuals to ALD. The outcome of this research is expected to provide critical information for developing more comprehensive mechanistic studies to further our understanding of the as yet unknown mechanisms of ALD. The results are also expected to aid in early detection and development of appropriate therapies for humans with ALD.

Public Health Relevance

This investigation will characterize the development of alcoholic liver disease (ALD) in mice with deficiency of a protein, augmenter of liver regeneration (ALR). Unlike any other animal models, our newly developed genetically engineered novel ALR-deficient mouse develops human-like ALD (including fibrosis). Since only 10-35% alcoholics develop end-stage ALD, we will also explore the possibility of any variations in human ALR gene that predisposes this population to end-stage ALD. The outcome of this exploratory research is expected to provide critical information for more comprehensive mechanistic future studies to further our understanding of the as yet unknown mechanisms of ALD. The results are also expected to aid in early detection and development of appropriate therapies for humans with ALD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Health Services Research Review Subcommittee (AA)
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Radaeva, Svetlana
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Cincinnati Children's Hospital Medical Center
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Nalesnik, Michael A; Gandhi, Chandrashekhar R; Starzl, Thomas E (2017) Augmenter of liver regeneration: A fundamental life protein. Hepatology 66:266-270
Dangi, Anil; Huang, Chao; Tandon, Ashish et al. (2016) Endotoxin-stimulated Rat Hepatic Stellate Cells Induce Autophagy in Hepatocytes as a Survival Mechanism. J Cell Physiol 231:94-105
Gandhi, Chandrashekhar R; Chaillet, J Richard; Nalesnik, Michael A et al. (2015) Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice. Gastroenterology 148:379-391.e4
Vodovotz, Yoram; Prelich, John; Lagoa, Claudio et al. (2012) Augmenter of liver regeneration (ALR) is a novel biomarker of hepatocellular stress/inflammation: in vitro, in vivo and in silico studies. Mol Med 18:1421-9