{"doi":"10.1016/j.apsb.2021.08.024","title":"Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk","abstract":"We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.","journal":"Acta Pharmaceutica Sinica B","year":2021,"id":175651,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9497,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":513704,"name":"Stefanie Kennon‐McGill","orcid":"0000-0001-8913-8214","position":1,"is_corresponding":false},{"id":513703,"name":"Joel H. Vazquez","orcid":"0000-0002-3033-1914","position":2,"is_corresponding":false},{"id":484900,"name":"Owen Stephens","orcid":"0000-0001-8400-2916","position":3,"is_corresponding":false},{"id":572512,"name":"Erich A. Peterson","orcid":"0000-0003-0925-7243","position":4,"is_corresponding":false},{"id":283869,"name":"Donald J. Johann","orcid":null,"position":5,"is_corresponding":false},{"id":417656,"name":"Felicia D. Allard","orcid":"0000-0001-9903-0944","position":6,"is_corresponding":false},{"id":406870,"name":"Eric U. Yee","orcid":"0000-0001-9643-6439","position":7,"is_corresponding":false},{"id":514324,"name":"Sandra McCullough","orcid":null,"position":8,"is_corresponding":false},{"id":342566,"name":"Laura P. James","orcid":"0000-0002-4266-3924","position":9,"is_corresponding":false},{"id":258412,"name":"Brian N. Finck","orcid":"0000-0001-5411-3674","position":10,"is_corresponding":false},{"id":282112,"name":"Mitchell R. McGill","orcid":"0000-0002-0401-0463","position":11,"is_corresponding":false},{"id":513702,"name":"Melissa M. Clemens","orcid":"0000-0002-5282-9852","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:47:15.431199Z","pmid":"35024310","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":[]}