The two hit theory of NAFLD progression. Current literature indicates that the crucial derangement in NAFLD is represented by insulin resistance (IR), which is a key feature of the metabolic syndrome, a clinical entity that also includes type 2 diabetes mellitus, hypertrigliceridemia, hypertension, a decreased level of high-density lipoprotein and obesity. Indeed, as suggested by several authors, steatosis may simply represent the hepatic manifestation of the metabolic syndrome ([143, 144] and references therein). The first hit is a metabolic one dominated by IR, with NAFLD being associated with both hepatic and adipose tissue IR as well as reduced insulin sensitivity of the whole human body [143, 144, 146]. This can lead from one side to 1) a significant reduction of glucose disposal and to a lack of suppression of hepatic glucose production as well as 2) a defect of disposal of free fatty acids (FFAs) at the adipocyte level (and skeletal muscle) that, in turn, 3) will open the way to high circulating levels of FFAs (and hypertrigliceridemia) coming from either subcutaneous and visceral fat, which will cause a persistent excess delivery of FFAs to the liver, the ultimate cause of liver steatosis [142–146]. Molecular details on how the excess load of FFAs to hepatocytes can lead to steatosis can be found in more specialized reviews [142, 143], with increased de novo synthesis of fatty acids and triglycerides as well as both impaired oxidation (mitochondrial plus peroxisomal) and impaired efflux of fatty acids (by reduced synthesis of Apo-B100 or transport of VLDL particles) being the candidate responsible processes.