{"doi":"10.1016/j.redox.2022.102570","title":"Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease","abstract":"BACKGROUND AND AIMS: Caloric excess and sedentary lifestyles have led to an epidemic of obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). The objective of this study was to investigate the mechanisms underlying high fat diet (HFD)-induced NAFLD, and to explore NRF2 activation as a strategy to alleviate NAFLD. APPROACH AND RESULTS: Herein, we demonstrated that high fat diet (HFD) induced lipid peroxidation and ferroptosis, both of which could be alleviated by NRF2 upregulation. Mechanistically, HFD suppressed autophagosome biogenesis through AMPK- and AKT-mediated mTOR activation and decreased ATG7, resulting in KEAP1 stabilization and decreased NRF2 levels in mouse liver. Furthermore, ATG7 is required for HFD-induced NRF2 downregulation, as ATG7 deletion in Cre-inducible ATG7 knockout mice decreased NRF2 levels and enhanced ferroptosis, which was not further exacerbated by HFD. This finding was recapitulated in mouse hepatocytes, which showed a similar phenotype upon treatment with saturated fatty acids (SFAs) but not monounsaturated fatty acids (MUFAs). Finally, NRF2 activation blocked fatty acid (FA)-mediated NRF2 downregulation, lipid peroxidation, and ferroptosis. Importantly, the HFD-induced alterations were also observed in human fatty liver tissue samples. CONCLUSIONS: HFD-mediated autophagy inhibition, NRF2 suppression, and ferroptosis promotion are important molecular mechanisms of obesity-driven metabolic diseases. NRF2 activation counteracts HFD-mediated NRF2 suppression and ferroptotic cell death. In addition, SFA vs. MUFA regulation of NRF2 may underlie their harmful vs. beneficial effects. Our study reveals NRF2 as a key player in the development and progression of fatty liver disease and that NRF2 activation could serve as a potential therapeutic strategy.","journal":"Redox Biology","year":2022,"id":236077,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":73,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228192,"name":"Annadurai Anandhan","orcid":"0000-0002-2140-1183","position":1,"is_corresponding":false},{"id":855851,"name":"Jinjing Chen","orcid":"0000-0002-8211-8963","position":2,"is_corresponding":false},{"id":637023,"name":"Aryatara Shakya","orcid":"0000-0001-5309-9436","position":3,"is_corresponding":false},{"id":66207,"name":"Matthew Dodson","orcid":"0000-0002-3743-5476","position":4,"is_corresponding":false},{"id":300873,"name":"Aikseng Ooi","orcid":"0000-0002-3451-0717","position":5,"is_corresponding":false},{"id":300874,"name":"Eli Chapman","orcid":"0000-0002-6310-1664","position":6,"is_corresponding":false},{"id":244442,"name":"Eileen White","orcid":"0000-0003-2961-3065","position":7,"is_corresponding":false},{"id":300875,"name":"Joe G. N. Garcia","orcid":"0000-0002-6934-0420","position":8,"is_corresponding":false},{"id":228195,"name":"Donna D. Zhang","orcid":"0000-0002-8972-697X","position":9,"is_corresponding":false},{"id":106765,"name":"Pengfei Liu","orcid":"0000-0003-1003-2025","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T00:21:58.728756Z","pmid":"36495698","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}