fig1

Figure 1. Multiple-hit hypothesis of the progression of NAFLD/NASH. Dietary habits, environmental, and genetic factors cause overweight or obesity and change the intestinal microbiome. This results in increased serum FFA and inflammatory factor (adipo-, cyto- and/or chemokines) levels and eventually leads to insulin resistance. Furthermore, insulin resistance leads to an increase in DNL in the liver and increases the synthesis and accumulation of TG and toxic levels of fatty acids. Fat accumulation in the liver in the form of TG leads to liver steatosis (NAFL). Free cholesterol and other lipid metabolites cause mitochondrial dysfunction and subsequent oxidative stress, and ROS release and ER stress further activates UPR; which collectively lead to hepatic inflammation and fibrosis (NASH). NAFLD: Nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; FFAs: free fatty acids; DNL: de novo lipogenesis; LPS: lipopolysaccharide; TNFα: tumor necrosis factor alpha: IL-6: interleukin-6; TG: triglycerides; ER: endoplasmic reticulum; UPR: unfolded protein response; ROS: reactive oxygen species.