Circadian control of hepatic ischemia/reperfusion injury via HSD17B13-mediated autophagy in hepatocytes

Background & Aims: Studies have illustrated the role of circadian rhythms in hepatic ischemia/reperfusion injury (HIRI), but the mechanisms are poorly understood. Bmal1 plays a significant role in the circadian control of liver physiology and disease; however, its role in HIRI has not been investigated. Here, we aimed to explore the potential contribution of BMAL1 to HIRI. Methods: The impact of ischemia/reperfusion timing (Zeitgeber time [ZT]0 vs. ZT12) on liver damage was assessed in mice with Bmal1 specifically depleted in hepatocytes or myeloid cells. RNA sequencing and other techniques were employed to explore the underlying molecular mechanisms. Additionally, we investigated the role of HSD17B13, a lipid droplet-associated protein, in BMAL1-mediated circadian control of HIRI by utilizing global knockout, hepatocyte-specific knockdown, or hepatocyte-specific humanized HSD17B13 overexpression mouse models. Results: We found that initiating ischemia/reperfusion operations at ZT12 instead of ZT0 resulted in significantly more severe liver injury in wild-type mice. Bmal1 in hepatocytes, but not in myeloid cells, mediated this temporal difference. Mechanistically, BMAL1 regulates the diurnal oscillation of HIRI by directly controlling Hsd17b13 transcription via binding to E-box-like elements. Hepatocyte-specific knockdown of Hsd17b13 blunted the diurnal variation of HIRI and exacerbated ZT0 HIRI. Furthermore, depletion of the BMAL1/HSD17B13 axis may inhibit lipid degradation by blocking autophagy flux, contributing to lipid overload and exacerbating HIRI. Finally, we demonstrated that hepatocyte-specific overexpression of humanized HSD17B13 may confer protection during ZT0 HIRI but aggravate damage at ZT12. Conclusions: Our study uncovers a pivotal role of hepatocyte BMAL1 in modulating circadian rhythms in HIRI via HSD17B13-mediated autophagy and offers a promising strategy for preventing and treating HIRI by targeting the BMAL1/HSD17B13 axis. Impact and implications: This study unveils a pivotal role of the BMAL1/HSD17B13 axis in the circadian control of hepatic ischemia/reperfusion injury, providing new insights into the prevention and treatment of hepatic ischemia/reperfusion injury. The findings have scientific implications as they enhance our understanding of the circadian regulation of hepatic ischemia/reperfusion injury. Furthermore, clinically, this research offers opportunities for optimizing treatment strategies in hepatic ischemia/reperfusion injury by considering the timing of therapeutic interventions.