Circadian Control of Hepatic Ischemia/Reperfusion Injury via HSD17B13-Mediated Autophagy in Hepatocytes

Abstract

Background & Aims

Studies have illustrated the role of circadian rhythm in hepatic ischemia/reperfusion injury (HIRI), but the mechanisms are poorly understood. Bmal1 is the most important gene that plays significant roles 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 (I/R) timing (ZT0 vs. ZT12) on liver damage were assessed in mice with Bmal1 specifically depleted in hepatocytes or myeloid cells. RNA sequencing and other multiple molecular biology experiments were employed to explore the 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 I/R operations at ZT12 resulted in significantly more severe liver injury in wild-type mice compared to ZT0. 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.