nonalcoholic fatty liver disease ( nafld ) is among the most common causes of chronic liver disease worldwide . the prevalence of nafld in the general population of western countries is 2030% . within the spectrum of nafld , only nonalcoholic steatohepatitis ( nash ) most patients with nafld have risk factors such as insulin resistance , obesity or other indications of metabolic syndrome . insulin resistance , oxidative stress , and inflammatory cascades are believed to play integral roles in the pathogenesis and progression of nafld . as such , a  multi - hit  ( formerly  double - hit  ) hypothesis has been used to describe the pathogenesis of nafld . as a result of the first insulin resistance arises and increased fatty acid levels in the blood enter the liver ( and/or are not removed from the liver ) , thus leading to hepatosteatosis . the second  hit  occurs as a result of the inflammation caused by the hepatosteatosis . the criterion standard method for the diagnosis of nafld , which most frequently presents with an asymptomatic increase of transaminase enzymes , is a liver biopsy . despite evidence that weight loss , dietary modifications , bariatric surgical operations , exercise and several drugs result in the biochemical and histological resolution of nafld , there is no current treatment regimen supported by valid , long - term studies that were properly randomized and controlled [ 710 ] . currently , the basis for treatment includes managing risk factors such as hyperlipidemia through steps such as lifestyle modification and weight loss . sirt1 is an nad - dependent deacetylase and acts as a modulator of various metabolic pathways . in this article , we focus on the sirtuin 1 ( sirt1 ) protein , which has important effects on glucose homeostasis , lipid mobilization , -oxidation , oxidative stress , insulin secretion and sensitivity , inflammation , cellular aging and apoptosis . we discuss the expression of sirt1 in cases of nafld , the results of sirt1 activation and the potential therapeutic role for sirt1 in treating nafld . silent information regulator 2 ( sir2 ) proteins , or sirtuins , are a class of proteins that possess either histone deacetylase or mono - adp - ribosyl transferase activity . they are found in organisms ranging from bacteria to humans . sirt1 , an nad - dependent protein deacetylase , is an important regulator of energy homeostasis in response to nutrient availability . currently , the best - studied sirtuin homolog , sirt1 , is expressed in metabolic tissues such as liver , skeletal muscle , adipose tissue , pancreas and brain ; its actions in these tissues include regulation of -cell and neuron survival , hepatic gluconeogenesis , insulin secretion and adiposity . resveratrol ( trans-3,5,4-trihydroxystilbene ) is a polyphenol found in red wines and a wide variety of plants including grapes , berries and peanuts . resveratrol has been shown to be a potent agonist of sirt1 [ 1315 ] . in mammalian cells , resveratrol promotes cellular expression of the sirt1 protein and dramatically stimulates sirt1 activity . furthermore , small - molecule sirt1 activators with structures unrelated to resveratrol but with 1000 times the potency have been identified . the effects of sirt1 activation , especially in metabolic tissues , lead to the inhibition of various pathways important for nafld pathogenesis . the liver is the central metabolic organ and regulates several key aspects of lipid metabolism ( fatty acid -oxidation , lipogenesis and lipoprotein uptake and secretion ) in response to nutritional and hormonal signals . nutritional intake in excess of the -oxidation capacity of the cell , lipoprotein synthesis and defects in excretion form the foundation of hepatosteatosis . over time , the transcriptional network of the liver contributes to an inflammatory process that progressively leads to nash associated with fibrosis , liver cirrhosis , hepatocellular carcinoma and death due to liver disease . in several recent studies , sirt1 has been shown to play an important role in the dynamics of nafld pathophysiology . using an experimental nafld model consisting of rats fed a high - calorie diet , another study in rats with nafld showed a significant increase in hepatic sirt1 expression and histological improvement with calorie limitation . in a study by purushotham et al . , hepatocyte - specific loss of sirt1 ( through hepatocyte - specific deletion of sirt1 ) was shown to cause peroxisome proliferator - activated receptor  ( ppar ) signal failure and a decrease in fatty acid -oxidation . however , sirt1 overexpression increased levels of ppar and its coactivator ppar coactivator 1 ( pgc-1 ) . pgc-1 impairs ppar signaling and decreases fatty acid -oxidation , whereas overexpression of sirt1 induces the expression of ppar s targets . sirt1 interacts with ppar and is required to activate the ppar coactivator pgc-1. in a recently reported study in rats , sirt1 was shown to confer protection against age - associated metabolic damage , lead to healthier aging , decrease the frequency of liver cancer related to metabolic syndrome and protect the liver from carcinogenic damage . studies performed at the molecular level have demonstrated that sirt1 plays an important role in the regulation of the transcriptional networks controlling various critical metabolic processes in the liver [ 2426 ] . along those lines , sirt1 has been shown to deacetylate many nonhistone proteins , including p53 , nuclear factor kappa b ( nf-b ) , forkhead box class o 3 ( foxo3 ) transcription factors , pgc-1 , liver x - receptor ( lxr ) , clock , per2 and torc2 [ 2736 ] . in a study by yamazaki et al . , treatment of mice modeling nafld with a sirt1 activator ( srt1720 ) resulted in decreases in expression of lipogenic genes ( such as those encoding sterol regulatory element - binding protein-1c [ srebp-1c ] , acyl - coa carboxylase [ acc ] and fatty acid synthase [ fas ] ) , serum lipid profile , fat accumulation in the liver , expression of genes related to oxidative stress and the production of inflammatory cytokines . in a study of bariatric surgical cases performed by costa et al . , morbidly obese patients with severe hepatosteatosis were determined to have reduced expression of sirt1 in adipose tissue when compared to patients with mild hepatosteatosis . recent studies have shown that sirt1 plays important roles in both insulin resistance and insulin regulation in diabetics ( such as increasing insulin secretion from pancreatic -cells , stimulating lipolysis in adipose tissue and increasing glucose utilization in muscle tissue ) . in pancreatic -cells , sirt1 has been shown to increase insulin secretion through the repression of uncoupling protein 2 ( ucp2 ) . it was also demonstrated that sirt1 activation increases atp production in -cells and improves glucose - dependent insulin secretion , which typically decreases with age . a recent study demonstrated that inhibiting sirt1 overexpression and nf-b signaling decreases cytokine - induced pancreatic -cell damage . as a result , sirt1 activation prevents the development of insulin resistance and limits the pancreatic -cell dysfunction that develops in response to insulin resistance . it has been shown that sirt1 activation increases lipolysis by repressing ppar in adipose tissue , thereby inhibiting adipogenesis . sirt1 also regulates the production and/or secretion of insulin - sensitizing factors such as adiponectin and fgf21 through the regulation of foxo1 and ppar [ 4345 ] . lxrs regulate the transfer of cholesterol from peripheral tissues to the liver ( reverse cholesterol transport ) . pgc-1 deacetylation by sirt1 in skeletal muscle is necessary for the activation of mitochondrial fatty acid oxidation genes . as further evidence of the important of sirt1 in muscle , patients with type 2 diabetes show reduced expression of pgc-1 and mitochondrial oxidative phosphorylation ( oxphos ) genes in skeletal muscle . based on these data , the sirt1-dependent activation of pgc-1 sun et al .   showed that sirt1 improves insulin sensitivity in skeletal myotubes through transcriptional repression of the protein tyrosine phosphatase 1b ( ptp1b ) gene . ptp1b is a key insulin receptor phosphatase , and ptp1b - deficient mice have been shown to be more insulin - sensitive and more resistant to diet - induced obesity compared to controls . recent studies have begun to address the relationship between sirtuins and age - related metabolic and cardiovascular diseases , antiinflammatory properties , anticarcinogenic effects , effects on oxidative stress and the cell cycle and anti - aging effects . epidemiological evidence gathered from nafld patients demonstrates that both cardiovascular disease risk and mortality are significantly increased when compared to a normal population [ 5355 ] . the cause of these effects may include vascular relaxation ( both by increasing endothelial nitric oxide synthase activity and by potassium channel - mediated vasorelaxation ) , inhibition of thrombocyte aggregation or increasing cardiac myocontractility ( by pgc-1 regulation ) [ 5660 ] . in addition , individuals with a single nucleotide polymorphism in the sirt1 gene exhibit a lower incidence of cardiovascular mortality , myocardial infarction , myocardial ischemia , stroke , arterial surgery and intermittent claudication . one of the important stages in the pathophysiology of nafld is the inflammatory process , which is considered the . one important effect of sirt1 activation , which was discovered recently , is its anti - inflammatory effect . an important aspect of this effect is performed through regulation of nf-b ( a master transcription factor involved in the regulation of proinflammatory cytokines and a key part of nafld pathogenesis ) . recent studies have shown that sirt1 also deacetylates and suppresses the transcriptional activity of activator protein-1 ( ap-1 ) , leading to a down - regulation of cyclooxygenase-2 ( cox-2 ) gene expression . in addition , the expression of multiple proinflammatory mediators , such as intracellular adhesion molecule 1 ( icam1 ) , mcp1 , rantes ( also known as ccl5 ) , macrophage colony stimulating factor ( m - csf ) , granulocyte - macrophage csf ( gm - csf ) , g - csf , and transforming growth factor- ( tgf- ) , is reduced by the sirt1 activator resveratrol . thus , sirt1 activity results in antiinflammatory effects through its regulation of multiple inflammatory pathways . another characteristic of sirt1 activation , discovered in the last few years , is its effects on tumorigenesis . the antiproliferative , proapoptotic and tumor suppressing effects of sirt1 activation have been elucidated by studies performed in rats . additionally , use of sirt1 in cancer chemotherapy , based on its chemopreventive effects , has been considered . resveratrol has been shown to have anti - carcinogenic effects both in vitro and in vivo . sirt1 has been shown to indirectly reduce the cellular oxidative stress burden through deacetylation of foxo3 ( deacetylation of foxo3 leads to upregulation of catalase and mnsod ) . sirt1 has also been shown to control the cell cycle , cell differentiation , cell proliferation and cell senescence by its regulation of the foxo and p53 proteins . a sedentary lifestyle and variations in dietary habits has significantly increased the frequency of metabolic syndrome and its hepatic component , nafld , and the number of patients with this condition continues to rise . currently , there is no validated evidence - based treatment algorithm , and patients are currently treated with recommendations for caloric limitation and increased physical activity . in recent years , the positive effects of sirt1 activation have been shown in the metabolic activities related to nafld pathophysiology . these activities include glycemic regulation , lipid homeostasis , insulin secretion and sensitivity , inflammatory processes , oxidative stress , endothelial dysfunction , mitochondrial biogenesis and -oxidation , cellular senescence , autophagy / apoptosis and skeletal and heart muscle function . from these results , we believe that sirt1 activation has potential as a therapeutic target to prevent both the progression and development of nafld . recent studies have demonstrated the positive effects of sirt1 activation on these metabolic activities after induction by resveratrol , a natural polyphenol . in addition , sirt1 activators that are 1000 times more efficient than resveratrol are currently being developed and studied . current policy requires that therapeutic efficiency and security profile evaluations in randomized controlled studies be performed for new pharmaceutical agents .