Mitochondrial ALR Protein Deficiency Drives Progressive Alcoholic Liver Disease
Abstract
Chronic alcohol abuse is on the rise among Veterans and military Service members. A significant number of alcoholics develop liver fibrosis and cirrhosis, for which liver transplantation is the only lifesaving option. Because currently there are no specific biomarkers indicative of the predisposition to alcohol-induced cirrhosis, the disease progresses silently. Moreover, we do not know the specific biochemical mechanisms of why only this subpopulation is adversely affected by chronic alcohol consumption. Therefore, the objective of this proposal is to identify reliable biomarker(s) as well as to delineate as yet unidentified crucial mechanisms for early diagnosis and intervention of the progressive alcoholic liver disease. Our published and preliminary work suggests that genetic deficiency or abnormality in a protein that has critical mitochondrial function can be a major predisposing factor for aggressive alcoholic liver disease. This protein is known as “Augmenter of Liver Regeneration (ALR).” We have generated genetically engineered ALR-deficient mice of two types. One has normal liver despite subnormal but physiologically adequate mitochondrial function. These mice when subjected to alcohol consumption develop excessively fatty liver and fibrosis. Normal mice develop only moderately fatty liver and no fibrosis. The other mouse with ALR-deficiency has moderate liver disease and develops cirrhosis when placed on alcohol-supplemented diet. Both of these mouse models are highly relevant to human alcoholic chronic liver disease. Our preliminary work also shows that humans with alcoholic steatohepatitis have lower than normal blood ALR levels, which decrease even further in alcoholic cirrhosis. We have identified certain abnormalities in human ALR gene, presence of which in alcoholics might be the causal for aggressive liver disease. Experiments described in this proposal are aimed (1) to identify precisely how ALR deficiency or abnormality drives alcoholic liver disease and its association with mitochondrial dysfunction; (2) to ascertain whether blood ALR levels can be a biomarker of disease predisposition; (3) to ascertain whether specific genetic abnormalities are associated with aggressive liver disease; and (4) to ascertain whether ALR treatment reverses progression of the disease. Fiscal Year 2019 (FY19) Peer Reviewed Medical Research Program (PRMRP) Topic Area(s) addressed by the proposed research project: Mitochondrial dysfunction or injury is a critical component of alcoholic liver disease. The proposed research project addresses FY19 PRMRP “Mitochondrial Disease” Topic Area because ALR has critical mitochondrial function(s), and its mitochondrial deficiency subjects the cells to be vulnerable to stress such as that by alcohol. Mitochondrial injury due to combination of ALR deficiency and alcohol exposure leads to excessive fat accumulation and cellular injury that trigger activation of cells (known as stellate cells), which then produce excessive amounts of extracellular matrix causing liver fibrosis. The ultimate applicability and impact of the research: We expect that the outcome of this research will be highly applicable in early identification and timely treatment of alcoholic liver disease from its progression to irreversible cirrhosis. With increasing incidence of chronic alcohol abuse among the Veterans and military Service members, the impact of this research is very high. What types of patients will help, and how will it help them? The findings of this research are expected to be helpful for alcoholics in early diagnosis, thus providing a chance for timely treatment to prevent disease progression to irreversible damage. What are the potential clinical applications and benefits? Potential clinical application of this research is early diagnosis of alcoholic liver disease in patients that are predisposed to irreversible damage (blood ALR levels and/or genetic abnormality) and t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010477
Entities
People
- Chandrashekhar R Gandhi
Organizations
- United States Army