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ARRA Investments in Alcohol-Induced Metabolic and Hepatic Injury

Public Health Burden
Virtually every organ system in the body is vulnerable to damage induced by excessive or chronic alcohol use, damage which results in a range of medical conditions. These conditions include liver disease, pancreatitis, heart disease, fetal abnormalities and brain damage, and produce an enormous economic and public health burden.  In addition, alcohol-related organ damage is associated with an increased risk for certain types of cancer, especially esophageal and liver cancer.  Increased understanding of the mechanisms by which alcohol causes tissue injury and organ damage will inform the development of more effective treatment and prevention strategies and the identification of reliable, noninvasive tools for early diagnosis and monitoring of disease progression, thereby reducing health care costs.

Mechanisms of Alcohol-Induced Liver Injury
As the primary organ responsible for metabolism of alcohol, the liver is the main target of the toxic effects of chronic alcohol exposure.  Liver disease claims 37,000 lives annually; for approximately 40% of these deaths, alcohol is the underlying cause.  In 2008, alcoholic liver disease was responsible for nearly 20% of liver transplants in the U.S., making the development of treatment to prevent or reverse liver damage due to alcohol of paramount importance.  Research into the underlying mechanisms of injury could reveal potential targets for treatment, inform strategies for preventing tissue injury and improve the prognosis for alcohol-related liver disease.  ARRA supported research seeking to further elucidate these mechanisms include projects that will:
  • Investigate alcohol’s role in the impairments of mitochondrial and endoplasmic reticulum structure, function and signaling, and how the effect contributes to alcohol-induced tissue injury.1 In addition, the differential effects of alcohol on mitochondria that lead to cardiomyopathy (disease of the heart muscle) will be studied based on age and gender.2
  • Investigate the mechanisms by which key signaling pathways interact to produce synergistic liver cancer in alcohol abusing individuals also infected with hepatitis C virus.3
  • Since alcohol metabolism in the liver impairs the metabolism of retinoids that play a role in the molecular mechanisms of autoimmune diseases, a project will investigate the role of retinoids (vitamin A and its metabolites) in the development of alcohol-induced tissue/organ injury.4
  • Determine gene expression profiles associated with nonalcoholic fatty liver disease, alcoholic fatty liver disease and chronic hepatitis C infection.  This project will take advantage of samples already collected from hepatitis C patients, with history of alcohol consumption, and will pave the way for developing biomarkers for alcohol-induced liver damage.5
Biomarkers to detect alcohol induced injury in various tissues and organs could facilitate early diagnosis, leading to earlier medical intervention and improved outcomes, and improve monitoring of disease progression and effectiveness of treatment.  Research on biomarkers may also lead to a deeper understanding of the mechanisms of alcohol-induced tissue and organ injury.  Although several alcohol biomarkers have been identified and are currently used in clinical practice, their utility is limited because they lack accuracy, specificity and/or sensitivity.   Examples of ARRA funded projects seeking new biomarkers include those that:
  • Utilize a proteomics/metabolomics approach to identify biomarkers for steatohepatitis (fatty liver accompanied by inflammation and fibrosis - an antecedent of liver cirrhosis), including biomarkers unique to alcohol-induced steatohepatitis that could predict disease outcomes in various ethnic populations.6
  • Determine whether changes in systemic immunity and lipid metabolism initiated by microbial changes in the intestine contribute to alcohol-induced tissue injury and liver dysfunction, and identify alcohol-related biomarkers of intestinal, immune and metabolic derailments characteristic of alcohol-induced liver injury.7

  1. 1RC2AA019416-01 -- ER mitochondrial signaling and alcoholic tissue injury -- Hajnoczky, Gyorgy (contact); Hoek, Joannes B (PA)
  2. 1RC2AA019403-01 -- Novel Mitochondrial Mechanisms of Ethanol-Induced Cardiac Injury in Aged Females -- Korzick, Donna Hope (PA)
  3. 1RC2AA019392-01 -- TLR4 and TGF-beta interactions in HCC induced by HCV and alcohol -- Tsukamoto, Hidekazu (CA)
  4. 1RC2AA019413-01 -- Retinoid Metabolism and Alcohol Induced Disease -- Blaner, Williams S (NY)
  5. 1RC2AA019399-01 -- Characterizing Alcohol's Effects on Repair of Liver Injury -- Diehl, Anna Mae Elizabeth (NC)_
  6. 1RC2AA019385-01 -- Biomarkers for Steatohepatitis -- McClain, Craig J (KY)
  7. 1RC2AA019405-01 -- Systems Biology Approach to Identifying Biomarkers for Alcoholic Liver Disease -- Gillevet, Patrick Martin; Keshavarzian, Ali (contact) (IL)

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