Alcohol significantly reduces SIRT1 and SIRT5 expression [30, 31, 33–35]: cytoplasmic SIRT1 and mitochondrial SIRT5 are (NAD+)-dependent deacetylase that regulate the activity of histonic and nonhistonic proteins [36, 37]. They are important regulators of energy metabolism controlling the gluconeogenic genes and hepatic glucose output through PGC-1α deacetylation (and hence the gluconeogenesis/glycolitic pathway) [30, 31, 38–40]; in addition, SIRT1 modulates the effects of PGC-1α repression of glycolytic genes in response to fasting and pyruvate [39]. Knockdown of SIRT1 in liver causes mild hypoglycemia, increases systemic glucose and insulin sensitivity, and decreases glucose production. SIRT1 knockdown also decreases serum cholesterol and increases hepatic free fatty acids (FFAs) and cholesterol content [40]. Ethanol administration induces PGC-1α and p53 hyperacetylation that could be partially ascribed to SIRT1 and SIRT5 reduced expression; posttranslational modifications of these proteins inactivate PGC-1α and p53 physiological functions and are associated with mitochondrial dysfunction [30, 31]. Sirtuins may also regulate lipid metabolism: SIRT-1 mediates SBREP-1 activation by ethanol regulating its acetylation. In fact, inhibition of hepatic SIRT1 activity is associated with an increase in the acetylated active nuclear form of
