Sleep deprivation drives hepatic steatosis via sympathetic sprouting-induced ER stress in young male mice

BACKGROUND & AIMS: Accumulating evidence indicates that sleep loss is significantly associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the underlying mechanisms remain poorly understood. This study aimed to investigate the role of hepatic sympathetic nerves in sleep loss-associated MASLD. METHODS: Chronic sleep restriction (CSR) was induced using an automated cylindrical sleep-deprivation apparatus with a rotating bar. The 3D architecture of hepatic sympathetic nerves was visualized using the iDISCO+ (immunolabeling-enabled 3D imaging of solvent-cleared organs) volume immunoimaging technique. Liver-to-body weight ratios, histological features, and biochemical parameters were compared between CSR mice treated with 6-hydroxydopamine for chemical sympathetic denervation and vehicle-treated CSR mice. IRE1α-XBP1s signaling activity was assessed in hepatocyte cell lines and liver tissues to explore underlying mechanisms. RESULTS: Mice subjected to sleep deprivation for 1 or 5 weeks developed hepatic steatosis, glucose intolerance, and insulin resistance. Using iDISCO+, CSR was shown to induce marked sympathetic axonal sprouting in the liver (n = 3 mice/group, p <0.05), accompanied by increased hepatic norepinephrine levels (n = 6-7 mice/group). Chemical sympathetic denervation significantly attenuated hepatic steatosis and liver injury in sleep-deprived mice (n = 5-6 mice/group, p <0.05). Mechanistically, activation of the IRE1α-XBP1s pathway was identified as a key mediator of adrenergic signaling that promoted hepatic lipid synthesis and accumulation (n = 4-5 mice/group). Furthermore, blockade of β-adrenergic receptors, but not α-adrenergic receptors, effectively suppressed CSR-induced hepatic steatosis. CONCLUSIONS: This study demonstrates that CSR induces sympathetic axonal sprouting in the liver, as revealed by advanced 3D imaging. Activation of the IRE1α-XBP1s pathway mediates sympathetic overactivity-driven hepatic steatosis, identifying a potentially targetable mechanism for MASLD therapy. IMPACT AND IMPLICATIONS: A growing body of evidence indicates that insufficient sleep duration is strongly associated with an increased risk of developing MASLD (metabolic dysfunction-associated steatotic liver disease), while the underlying mechanisms remain largely unclear. Our study revealed that sleep deprivation induces significant hepatic sympathetic sprouting with advanced 3D imaging, and identified the IRE1α-XBP1s pathway as a key downstream mediator of sympathetic overactivity in promoting hepatic steatosis and MASLD progression. Our findings highlight the critical role of sympathetic axon sprouting in response to chronic sleep restriction and advance our understanding of neural regulation of peripheral metabolism.