Circadian regulation of liver metabolism: experimental approaches in human, rodent, and cellular models

Circadian rhythms are endogenous oscillations with approximately a 24-h period that allow organisms to anticipate the change between day and night. Disruptions that desynchronize or misalign circadian rhythms are associated with an increased risk of cardiometabolic disease. This review focuses on the liver circadian clock as relevant to the risk of developing metabolic diseases including nonalcoholic fatty liver disease (NAFLD), insulin resistance, and type 2 diabetes (T2D). Many liver functions exhibit rhythmicity. Approximately 40% of the hepatic transcriptome exhibits 24-h rhythms, along with rhythms in protein levels, posttranslational modification, and various metabolites. The liver circadian clock is critical for maintaining glucose and lipid homeostasis. Most of the attention in the metabolic field has been directed toward diet, exercise, and rather little to modifiable risks due to circadian misalignment or disruption. Therefore, the aim of this review is to systematically analyze the various approaches that study liver circadian pathways, targeting metabolic liver diseases, such as diabetes, nonalcoholic fatty liver disease, using human, rodent, and cell biology models.