Liver clock: Malalignment and entrainment therapeutics

Table 1 Mechanism of liver clock misalignment and its mechanisms

Causes of misalignment of central and liver clock	Underlying mechanisms
Feeding time	Suprachiasmatic nucleus lacks expression of PPARα and glucagon receptors due to which it can’t respond to feeding cues; activation of liver PPARα combined with reduced insulin leads to RevErbα-mediated repression of BMAL1 and CRY, resulting in circadian clock misalignment
Irregular sleep timing	Transcriptional reprogramming of adipose tissue with increased lipogenesis and altered adipokine secretion
Night time light exposure	Decreased sympathetic output to brown adipose tissue
Temperature changes	Advanced liver circadian phase

PPARα: Peroxisome proliferator-activated receptor alpha.