I have been involved in alcoholism and liver research since the early 1980’s. This has included the study of effects of ethanol on intermediary metabolism in the liver and adipocytes, using cultured cells, and in vivo animal and human models. In addition, I have been closely involved in studies on the genetics of alcoholism, the epidemiology of alcohol use disorders, and human and animal studies of responses to alcohol, through my role as Director of the Indiana Alcohol Research Center. The Center has been funded for three decades.
We discovered that ethanol inhibits the activity of PPARα, activates SREBP1c, and inhibits AMP-dependent protein kinase (AMPK) in liver. The changes in the transcription factors and AMPK make the liver less capable of oxidizing fatty acids and induce fatty acid synthesizing enzymes. The inhibition of AMPK results in increased acetyl-CoA carboxylase activity and malonyl-CoA levels, blocking the ability of fatty acyl-CoA to enter the mitochondrion. More recently we have uncovered effects of alcohol use on ChREBP, which is relevant to the development of fatty liver from both alcohol and diet, and ceramide and protein phosphatase 2 (PP2A) that have implications for activation of stress kinases, and inhibition of anti-apoptotic pathways. These actions of alcohol on nuclear receptor signaling and stress kinases are directly relevant to the pathogenesis of alcoholic steatosis, alcoholic hepatitis, and likely to other forms of fatty liver, such as those related to obesity and diabetes (NAFLD and NASH) and to drug toxicity.
My involvement in the care of patients with alcoholism, research on pathogenesis of alcoholic liver injury, and my hepatology training led to involvement in organizing a multi-center consortium funded by the NIAAA to study the natural history and treatments for alcoholic hepatitis (TREAT: Translational Research and Evolving Alcoholic hepatitis Treatment) as well as performing mechanistic studies on the pathways leading to severe liver injury in human subjects. In addition, I have been involved in implementing screening for hazardous alcohol use (screening, brief intervention and referral to treatment) across the Eskenazi Health system.
Web Address: http://medicine.iupui.edu/IARC