Sympathetic activation links light exposure and rest-activity rhythm to liver injury and bile acid dysregulation

Prolonged light exposure and rest-activity alteration are increasingly prevalent in modern society, yet their health consequence and the underlying mechanism remain poorly characterized. The liver is an organ central to metabolic and circadian regulation. We hypothesized that extended wakefulness, which was modeled as long photoperiod in humans and short photoperiod in nocturnal mice, would affect liver integrity and function. Actigraphic watch, wheel running, morphological, biochemical, transcriptomic, and chromatographic techniques were employed to examine the impact of light exposure alteration. To reverse the circadian disorders mediated by the sympathetic nervous system (SNS) activation, SNS inhibitor or time-restricted feeding was applied. In both humans and mice, extended wakefulness increased daily activity and reduced rest, as well as inducing tissue injury exclusively in the liver and predominantly affecting bile acid metabolism. Mechanistically, short photoperiod enhanced hepatic sympathetic innervation and activity in mice, activating a norepinephrine-β2-adrenergic receptor-protein kinase A signaling axis that reprogrammed the hepatic circadian clock and bile acid metabolism. Chemical sympathectomy not time-restricted feeding restored bile acid rhythmicity and alleviated liver injury. These findings identified the liver as a primary target of circadian disruption and established elevated sympathetic tone as a key mediator linking extended light exposure to metabolic dysfunction.