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

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