Disrupted ER‐to‐Golgi trafficking underlies anti‐HIV drugs and alcohol‐induced cellular stress and hepatic injury

• DOI: 10.1002/hep4.1030
• Publication Date: 2017-03-27T11:55:33Z
• Authors: Hui Han; Yuxin He; Jay Hu; Rhema Lau; Harrison Lee; Cheng Ji
• Keywords: COPII; ATF6

Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in anti‐human immunodeficiency virus (HIV) drugs alcohol‐induced liver disease a significant number of patients infected with HIV. However, the precise mechanism by which alcohol cause ER remains elusive. We found that ritonavir‐boosted lopinavir (RL) activated two canonical UPR branches without activation third activating transcription factor 6 (ATF6) branch either HepG2 cells or primary mouse hepatocytes. In RL‐treated cells, ATF6 localization Golgi apparatus required for its was reduced; this followed fragmentation dislocation/redistribution Golgi‐resident enzymes. Severities induced other anti‐HIV varied were correlated response. mice fed RL, feeding deteriorated fragmentation, stress, elevated alanine aminotransferase, steatosis. The (GSR) markers GCP60 HSP47 increased knockdown immunoglobulin heavy‐chain enhancer 3 GSR small interfering RNA worsened RL‐induced cell death. Cotreatment pharmacological agent H89 RL inhibited enzyme dislocation stress. Moreover, coat complex II (COPII) complexes mediate ER‐to‐Golgi trafficking accumulated cells; not due to interference initial assembly COPII complexes. also reassembly short treatment removal brefeldin A. Conclusion : Our study indicates is disrupted and/or alcohol, contributes subsequent hepatic injury. ( Hepatology Communications 2017;1:122‐139)