Figure 3.

Major effects of heavy metals on the main pathways involved in NAFLD development. Dietary intake of heavy metals leads to impaired regulation of lipid metabolism, by promoting lipid synthesis and deposition and by inhibiting lipid catabolism. Heavy metals enhance DNL also through the increased transactivation of ChREBP, favoring TG synthesis and lipid deposition. Heavy metals impair mitochondrial functions and inhibit SIRT1, FAO, and autophagy, resulting in increased production of ROS and lipotoxicity, which in turn activate NLRP3 inflammasome and boost inflammation, further favoring NAFLD progression. Heavy metals contribute to NAFLD pathogenesis also by affecting gut permeability, thus increasing the flux of SCFA and inflammatory molecules toward the liver. The pathways/factors that increased or decreased are shown in red or blue, respectively. Abbreviations: ChREBP: carbohydrate responsive element binding protein; DNL: de novo lipogenesis; FAs: fatty acids; FAO: fatty acid oxidation; NLRP3: NLR family pyrin domain containing 3; ROS: reactive oxygen species; SCFA: short chain fatty acids; SIRT1: sirtuin 1; TG: triglyceride. Figure created with BioRender (https://biorender.com/, accessed on 11 May 2023).