ABSTRACT
Xenobiotics can activate the hepatic survival pathway, but it is not clear how impaired hepatic survival pathways may affect xenobiotic-induced liver injury. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a xenobiotic. Here we demonstrate that DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). Impaired autophagic flux was linked to a deregulated hepatic protein-chaperonin system and a significant decline in Rab family proteins. In addition, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the p62-Ub-IHB accumulation and cholestatic liver injury. Moreover, we showed that p62-Ub-IHB accumulation did not activate the proteostasis-related ER stress signaling pathway, but rather activated the NRF2 pathway and suppressed the FXR nuclear receptor, resulting in cholestatic liver injury. Conclusion: Impaired autophagy exacerbates xenobiotic-induced cholestatic liver injury. Promotion of autophagy may represent a new therapeutic approach for xenobiotic-induced liver injury.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial Support: The authors are in part supported by Lousiana BoR(BK), BeHeard Science Challenge(BK), ASIP/SROPP(BK), NIH/NIDDK grants R01 DK116605 (XMY). The funding sources do not participate in the study design or execution.
Conflict of Interest: The authors have declared that no conflict of interest exists.