*2.1. Carbohydrates*

Dietary carbohydrates, including free sugars, can promote the accumulation of liver fat by increasing intrahepatic triglyceride content [30] and the presence of some SNPs may involve an additive harmful effect. Among them, the most studied nutrient/dietgene interactions in clinical studies include the I148M variant of PNPLA3. Thus, in a cross-sectional study, Davis et al., reported a positive association between high dietary carbohydrate/sugar consumption and hepatic fat accumulation in Hispanic children with overweight and PNPLA3 GG genotype [31]. Similarly, Nobili et al., found that carriers of this genotype with a high consumption of sweetened beverages presented higher degrees of hepatic steatosis [32]. Furthermore, in a small clinical trial including 14 adolescents, GKRP rs1260326 TT variant increased de novo lipogenesis after glucose overload [33].

Particularly, the consumption of the monosaccharide fructose has been implicated in the development and progression of NAFLD [34]. Fructose triggers hepatic de novo lipogenesis via increasing the levels of lipogenic enzymes and stimulating sterol regulatory element-binding protein (SREBP)-1, and it also inhibits fatty acid oxidation, leading to an increase of reactive oxygen species (ROS) [35]. Thus, an ongoing clinical trial aims to evaluate the impact of fructose intake on liver lipogenesis in subjects with different genetic risk categories for NAFLD [36]. In a case control study, the combination of distinct gene variants related to oxidative stress mechanisms (glutathione S-transferase theta 1-GSTT1, glutathione S-transferase mu 1-GSTM1, sulfotransferase family 1A member 1-SULT1A1, cytochrome P450 2E1-CYP2E1 and cytochrome P450 1A1-CYP1A1) with high fruit/grilled food consumption increased the risk for NAFLD development [37]. In line with these results, previous studies have shown that high fructose diet promotes hepatic steatosis, oxidative stress and inflammation, leading to hepatocyte apoptosis [38]. The pathophysiology of fructose induced-NAFLD via oxidative stress encompasses several mechanisms, such as nonenzymatic reactions of fructose and ROS generation, hepatic phosphate deficiency and the production of harmful metabolites (e.g., methylglyoxal) [39]. In addition, the severity of liver injury by fructose may be mediated by the induced degree of mitochondrial dysfunction and oxidative damage [40]. On the other hand, the hepatic deleterious effects of fructose may be counteracted by some nutrients that prevent oxidative stress and increase the expression of antioxidant defense enzymes [41–45]. Dietary advanced glycation end products compounds found in grilled food have also been postulated to aggravate NAFLD via liver injury induced by chronic oxidative stress, and pharmacological and dietary strategies targeting the implied pathways could help to ameliorate NAFLD [46]. Therefore, the interaction between fructose/grilled food consumption and SNPs involved in oxidative stress may be crucial in NAFLD pathogenesis and resolution.
