Fumarates for Alcoholic Liver Disease

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Abstract Alcoholic liver disease (ALD) remains the leading lethal liver condition, and the primary reason for transplantation. There is still no effective therapy. Dimethyl fumarate (DMF), a monomethyl fumarate (MMF) prodrug, is an FDA proved therapy for neural degenerative diseases and has We have developed a novel analogue molecule nicotinamide fumarate (NMF) that carries optimized pharmacokinetic characters. Our preliminary data show that NMF significantly ameliorates alcoholic liver injury in mice, and is superior to DMF. been recently reported to rescue alcoholic liver injury in mice. We propose that NMF elicits its protection via three pathways: Nrf2-driven anti-oxidative reaction, Hca2-mediated anti-inflammatory response, and mitochondrial induction. In this study, we will evaluate the preventive and therapeutic efficacy of NMF comparing with RTA408 a drug solely inducing Nrf2, using mouse models of ALD. We will also identify the mechanistic signaling by focusing on Nrf2, Hca2 and mitochondrial functions. The study may lead to the development of new therapeutic modalities and translational studies in the future.