Figure 3.

Circadian rhythms and gut microbiota in the pathogenesis of NAFLD. Under normal physiological conditions, the central and peripheral clocks operate synchronously to maintain the normal operation of the body. Feeding time, sleep pattern, and aging cause circadian dysregulation, leading to alterations of microbiota diurnal rhythmicity, microbiota composition, and thus microbiota dysbiosis. Microbiota dysbiosis impairs gut barrier integrity and increases the gut permeability, which results in increased release of microbiota products such as endotoxin and microbiota metabolites into circulation. HFD or nutritional stress changes microbiota composition and circadian oscillation, increasing gut permeability and release of microbiota products. These microbiota products reach the liver and cause hepatic steatosis and inflammation, which are the features of NAFLD/NASH. Circadian disruption also directly causes dysregulation of liver metabolism, promoting NAFLD/NASH through increasing hepatic fat accumulation and inflammation.