{"doi":"10.1016/j.jlr.2025.100843","title":"The origin of hydroxy-cyclohexenone fatty acids from skin barrier protein and relevance to covalent binding of ceramides","abstract":"Lipid constituents of the skin permeability barrier include a portion of ceramides and fatty acids covalently bound to the barrier protein. The covalent binding requires enzymatic oxidation of linoleate (C18:2) esterified to skin-specific acylceramides, forming a reactive 9,10-epoxy-11E-13-keto derivative. Barrier proteins treated with alkali release the bound lipids and as described recently, including two prominent cyclic linoleate derivatives, C18 hydroxy-cyclohexenone fatty acids. Herein we addressed the origin of these cyclic products by alkali treatment of potential precursors. A UV-based assay indicated the rates of Michael adduction of 9,10-epoxy-11E-13-keto to cysteine are two orders of magnitude faster than for a typical unsaturated keto fatty acid, and 10-fold faster for the dihydroxy analog, rationalizing their biosynthesis for protein adduction. Alkali treatment degraded the epoxy-ketone and its cysteinyl (glutathione) adduct to multiple UV-absorbing products, although not including the hydroxy-cyclohexenones. By contrast, these derivatives were prominently produced from KOH treatment of the 9,10-dihydroxy-13-ketone or its glutathione adduct. As further evidence of the origin of the hydroxy-cyclohexenones, LC-MS quantitation showed a 90% reduction following KOH treatment of epidermis from mice deficient in Srd9c7, the dehydrogenase in the linoleate oxidation pathway. Taken together, the results confirm the hydroxy-cyclohexenones as derivatives of the linoleate oxidations in the skin barrier pathway and identify the dihydroxy-ketone as a component of the covalently-bonded lipids, and critical to integrity of the epidermal barrier.","journal":"Journal of Lipid Research","year":2025,"id":541493,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9405,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":158971,"name":"William E. Boeglin","orcid":null,"position":1,"is_corresponding":false},{"id":773015,"name":"Fumie Nakashima","orcid":null,"position":2,"is_corresponding":false},{"id":295362,"name":"Donald F. Stec","orcid":"0000-0001-9217-0362","position":3,"is_corresponding":false},{"id":416181,"name":"M. Wade Calcutt","orcid":"0000-0002-8002-4699","position":4,"is_corresponding":false},{"id":727302,"name":"Takuya Takeichi","orcid":"0000-0001-5958-2875","position":5,"is_corresponding":false},{"id":274966,"name":"Masashi Akiyama","orcid":"0000-0001-5863-9315","position":6,"is_corresponding":false},{"id":502252,"name":"Alan Brash","orcid":null,"position":7,"is_corresponding":false},{"id":1142912,"name":"Saori Noguchi","orcid":"0000-0002-0401-4480","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:52:47.161928Z","pmid":"40523623","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":[]}