Sirtuin 1 signaling and alcoholic fatty liver disease

Alcoholic fatty liver disease (AFLD) is one of the most prevalent forms of liver diseaseworldwide and can progress to inflammation (hepatitis), fibrosis/cirrhosis, and ultimately lead to endstage liver injury. The mechanisms, by which ethanol consumption leads to AFLD, are complicated andmultiple, and remain incompletely understood. Nevertheless, understanding its pathogenesis will facilitatethe development of effective pharmacological or nutritional therapies for treating human AFLD. Chronicethanol consumption causes steatosis and inflammation in rodents or humans by disturbing several importanthepatic transcriptional regulators, including AMP-activated kinase (AMPK), lipin-1, sterol regulatoryelement binding protein 1 (SREBP-1), PPARγ co-activator-1α (PGC-1α), and nuclear transcription factor-κB(NF-κB). Remarkably, the effects of ethanol on these regulators are mediated in whole or in part byinhibition of a central signaling molecule, sirtuin 1 (SIRT1), which is a nicotinamide adenine dinucleotide(NAD+, NADH)-dependent class III protein deacetylase. In recent years, SIRT1 has emerged as apivotal molecule controlling the pathways of hepatic lipid metabolism, inflammatory responses and inthe development of AFLD in rodents and in humans. Ethanol-mediated SIRT1 inhibition suppresses orstimulates the activities of above described transcriptional regulators and co-regulators, thereby deregulatingdiverse lipid metabolism and inflammatory response pathways including lipogenesis, fatty acid β-oxidation,lipoprotein uptake and secretion and expression of pro-inflammatory cytokines in the liver. This review aimsto highlight our current understanding of SIRT1 regulatory mechanisms and its response to ethanol-inducedtoxicity, thus, affirming significant role of SIRT1 signaling in the development of AFLD.