Katherine Byrnes: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA. ORCID
Niani Tiaye Bailey: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Kamal Baral: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Arissa Mercer: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Spandan Joshi: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Nickol Wahby: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Tyler Rorison: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Gang Liu: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Xiao-Ming Yin: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
Bilon Khambu: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA. bkhambu@tulane.edu. ORCID
Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a hepatotoxin. Here we demonstrate that hepatotoxin contained DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). An impaired autophagic flux was associated with a deregulated hepatic protein-chaperonin system and significant decline in Rab family proteins. Additionally, p62-Ub-IHB accumulation activated the NRF2 pathway rather than the proteostasis-related ER stress signaling pathway and suppressed the FXR nuclear receptor. Moreover, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the IHB accumulation and cholestatic liver injury. Conclusion: Impaired autophagy exacerbates hepatotoxin-induced cholestatic liver injury. The promotion of autophagy may represent a new therapeutic approach for hepatotoxin-induced liver damage.
References
J Cell Biol. 2010 Jan 25;188(2):253-69
[PMID: 20100911]
