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.

Table 2 Therapeutic and life style measures for realignment of liver clock

Management options	Mechanism	Remarks
Time restricted eating	Entrains liver clock with peripheral rhythms independent of central clock regulating key genes in lipid and glucose homeostasis	Aligns feeding to circadian phase; restricts intake to 6-10 hours
Morning light exposure	Entrains central clock with peripheral rhytms by neural and hormonal signals	Regulates SCN entrainment via melatonin and cortisol
Melatonin	Improves liver rhythm, especially during circadian disruption	Acts via MT1/MT2 receptors to influence peripheral clocks
Exercise timing (chrono-exercise)	Amplifies expression of liver clock genes like BMAL1, PER2	Time-of-day dependent AMPK/SIRT1 modulation
Nutrient timing (macronutrient scheduling)	Enhances clock-gene synchrony with metabolic cycles	Aligns insulin/glucose peaks with liver sensitivity. Prioritize protein breakfasts to leverage morning insulin sensitivity and aligning carbohydrate intake with afternoon liver glucose sensitivity reduces steatosis
Avoidance of night eating/shift work	Helps resynchronize liver rhythms	Prevents desynchrony of SCN and liver via feeding timing

SCN: Suprachiasmatic nucleus.