SEFA-6179, an Engineered Medium-Chain Fatty Acid, Prevents Alcoholic Liver Injury and Steatosis in a Murine Model of Alcohol-associated Liver Disease

Alcohol-associated liver disease (ALD) is one of the main causes of chronic liver injury often resulting in cirrhosis and liver transplant. Yet, no effective preventative therapy exists. Alcohol dehydrogenase (ADH) is the primary ethanol metabolizing enzyme in the liver, while Cytochrome P450 2E1 (CYP2E1) promotes oxidative liver injury. Structurally engineered fatty acid (SEFA)-6179, a medium chain fatty acid analogue, prevented cholestasis, steatosis, and fibrosis in a piglet model of intestinal failure-associated liver disease (IFALD), and has now completed Phase II trials. In this study, we used an acute on chronic alcohol-induced murine model to evaluate the effect of SEFA-6179 in preventing the progression of alcohol-induced liver injury. Measured outcomes included liver enzymes, histology, hepatic triglycerides concentrations, plasma ethanol levels, and interleukin-6 (IL-6). Liver alcohol metabolism was evaluated by measuring ADH, catalase, acetaldehyde dehydrogenase (ALDH) enzymatic activity, and CYP2E1 protein level. C57Bl/6 mice treated with SEFA-6179 had decreased plasma liver enzymes compared to vehicle at 9 hours post-ethanol binge. SEFA-6179 reduced histologic hepatosteatosis compared to vehicle. Additionally, SEFA-6179 treated mice had lower liver triglyceride concentration compared to vehicle. SEFA-6179 treated mice had lower ethanol concentration in conjunction with increased ADH activity and reduced alcohol-induced CYP2E1 elevation compared to vehicle. Treatment with SEFA-6179 lowered pro-inflammatory cytokine level (IL-6) compared to vehicle. SEFA-6179 mitigated liver injury and steatosis by upregulating ADH activity without increasing activity of the toxic secondary CYP2E1 metabolic pathway, warranting further investigation as a potential therapeutic in preventing the progression of ALD and reducing the need for liver transplantation.