Role of functional iron deficiency in alcohol-associated liver disease

PROJECT SUMMARY Alcohol-associated liver disease (ALD) accounts for approximately 45% of liver disease related deaths in the United States. However, there are no treatments for this significant health problem. A better understanding of the mechanisms underlying the progression from alcohol associated steatosis to hepatitis and cirrhosis would potentially lead to the development of novel therapeutic strategies for ALD treatment. Mitochondria plays an important role in supporting the oxidative metabolism of alcohol and acetaldehyde by expressing aldehyde dehydrogenase 2 (ALDH2) and regenerating NAD+, an essential cofactor for ALDH2 as well as alcohol dehydrogenase (ADH). Mitochondrial dysfunction is a hallmark change in chronic alcohol abuse and mediates exacerbated liver injury advancing the progression of ALD. However, the molecular foundation underlying ALD- associated mitochondrial abnormality remain to be elucidated. Iron is critical for mitochondrial respiration dependent on the biogenesis of iron-sulfur cluster (ISC) that mediates electron transfer in mitochondrial complex I-III. Our preliminary study identified that divalent metal transporter 1 (DMT1), an iron transporter that mediates endosomal iron exit and mitochondrial uptake, and frataxin (FXN), an essential mitochondrial iron chaperone that mediates ISC biogenesis, were markedly decreased in the liver of human patients with acute-on-chronic alcoholic hepatitis. This finding suggests that chronic alcohol consumption induces functional iron deficiency in the hepatocytes due to defective ISC biogenesis. Moreover, mice with hepatocyte-specific knockout of DMT1 displayed significantly increased liver injury and impaired alcohol metabolism. We thus hypothesize that chronic alcohol abuse induces hepatic FID-dependent mitochondrial dysfunction and impairment of alcohol metabolism promoting the progression of ALD. In Aim 1, we will identify the signature changes of hepatocellular iron metabolism in acute versus chronic alcohol drinking by utilizing chronic-plus-acute binge drinking mouse model and human liver samples and the cutting-edge multiplex microscopic analysis. Aim 2 will prove the detrimental role of functional iron deficiency as well as hepatic absolute iron deficiency in the pathogenesis of ALD by utilizing multiple hepatocyte-specific knockout mouse models. Aim 3 will attempt to unveil that endoplasmic reticulum stress of the hepatocytes induces DMT1/FXN downregulation impairing mitochondrial iron acquisition and ISC biogenesis in ALD. This exploratory study will demonstrate a paradigm-shifting concept that functional iron (ISC) deficit exerts strong adverse effects on alcohol-induced liver injury, shedding novel light on the development of new therapeutic modalities against ALD.