SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease.

ABSTRACT

Sirtuins are members of the silent information regulator 2 (Sir2) family, a group of Class III histone/protein deacetylases. There are 7 different sirtuins in mammals (SIRT1-7), of which SIRT1 is the best known and most studied. SIRT1 is responsible for the regulation of protein activation by means of deacetylating a variety of proteins that play important roles in the pathophysiology of metabolic diseases. Recently, it has been shown that SIRT1 plays key roles in the regulation of lipid and glucose homeostasis, control of insulin secretion and sensitivity, antiinflammatory effects, control of oxidative stress and the improvements in endothelial function that result due to increased mitochondrial biogenesis and ß-oxidation capacity. Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease, and it has been accepted as the hepatic component of metabolic syndrome. Recent studies have shown that SIRT expression in the liver is significantly decreased in an NAFLD model of rats fed a high-fat diet, and moderate SIRT1 overexpression protects mice from developing NAFLD. In addition to resveratrol, a natural SIRT1 activator, small-molecule pharmacologic SIRT1 activators have positive effects on metabolic diseases. These effects are particularly promising in the case of diabetes mellitus, for which phase studies are currently being performed. With this information, we hypothesized that the pharmacologic activation of SIRT1, which has been implicated in the pathogenesis of NAFLD, will be a potential therapeutic target for treating NAFLD. In this paper, we review the metabolic effects of SIRT1 and its association with the pathophysiology of NAFLD.