Alcoholic liver disease (ALD) is one of the primary causes of morbidity and mortality in the United States, which ranges from alcoholic fatty liver (AFL), cirrhosis, to hepatocellular carcinoma. AFL is characterized by accumulation of lipid in hepatocytes, which represents the initial stage of ALD. Chronic alcohol consumption can cause abnormal homocysteine (Hcy) and methionine (Met) metabolism, which in turn contributes to the development and progression of AFL. LncRNA H19 is paternally imprinted lncRNA, and is highly expressed in fetal liver but diminishes in adult liver. Of particular interest, such expression is reactivated in human chronic liver disease, implicating an important regulatory role in hepatic function and metabolism. Our preliminary results demonstrated that hepatic overexpression of H19 promoted alcohol induced liver injury and steatosis, which was associated with altered hepatic TG profiling and methionine levels, as revealed by lipidomics and metabolomics analyses. However, the physiological and molecular action of H19 in AFL remains largely unexplored and warrants further investigation. The overall objective is to elucidate the mechanistic function of H19 in alcoholic fatty liver. The central hypothesis is that H19 interacts with RNA binding protein polypyrimidine tract-binding protein (PTBP1) to inhibit bataine- homocysteine S-methltransferase (BHMT) expression and function, which disrupts homocysteine and methionine metabolism, leading to alcoholic fatty liver. We propose two specific aims to test the central hypothesis.
Aim #1 : To characterize the physiological role of H19 in alcoholic fatty liver.
Aim #2 : To elucidate the molecular mechanisms by which H19 induces alcoholic fatty liver. The proposed studies build on our long-standing experiences in studying liver metabolism and disease. We propose to use combined approaches of molecular biology, systems biology, genome wide high throughput and metabolomics analysis to investigate the novel regulatory role of IncRNA H19 in AFL. Therefore, the proposed study would be a pioneering investigation in integrating lncRNA function with methionine metabolism in AFL, providing advanced understanding of the pathophysiology of AFL.
Alcoholic liver disease (ALD) is a major cause of chronic liver diseases in the United States and is becoming a major health issue that is associated with the prevalence of obesity and diabetes. This study will uncover for the first time an important role of long non-coding RNA H19 in the regulation of alcoholic fatty liver, which is highly relevant to the mission of NIAAA.