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Multi-tissue profiling of oxylipins reveal a conserved up-regulation of epoxide:diol ratio that associates with white adipose tissue inflammation and liver steatosis in obesity.
Hateley, Charlotte; Olona, Antoni; Halliday, Laura; Edin, Matthew L; Ko, Jeong-Hun; Forlano, Roberta; Terra, Ximena; Lih, Fred B; Beltrán-Debón, Raúl; Manousou, Penelopi; Purkayastha, Sanjay; Moorthy, Krishna; Thursz, Mark R; Zhang, Guodong; Goldin, Robert D; Zeldin, Darryl C; Petretto, Enrico; Behmoaras, Jacques.
Afiliación
  • Hateley C; Centre for Inflammatory Disease, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK.
  • Olona A; Centre for Computational Biology and Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
  • Halliday L; Department of Surgery and Cancer, Imperial College London, UK.
  • Edin ML; Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC, USA.
  • Ko JH; Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
  • Forlano R; Department of Metabolism, Digestion and Reproduction, Imperial College London, UK; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK.
  • Terra X; Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, MoBioFood Research Group, Tarragona, Spain.
  • Lih FB; Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC, USA.
  • Beltrán-Debón R; Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, MoBioFood Research Group, Tarragona, Spain.
  • Manousou P; Department of Metabolism, Digestion and Reproduction, Imperial College London, UK; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK.
  • Purkayastha S; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK; University of Brunel, Kingston Lane, Uxbridge, London, UB8 3PH, UK.
  • Moorthy K; Department of Surgery and Cancer, Imperial College London, UK; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK.
  • Thursz MR; Department of Metabolism, Digestion and Reproduction, Imperial College London, UK; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK.
  • Zhang G; Department of Nutrition, College of Agriculture and Environmental Sciences, 3135 Meyer Hall, One Shields Avenue, UC Davis, Davis, CA, 95616, USA.
  • Goldin RD; Department of Metabolism, Digestion and Reproduction, Imperial College London, UK; Imperial College Healthcare NHS Trust, St. Mary's Hospital, Praed Street, London, W2 1NY, UK.
  • Zeldin DC; Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC, USA.
  • Petretto E; Centre for Computational Biology and Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore; Institute for Big Data and Artificial Intelligence in Medicine, School of Science, China Pharmaceutical University (CPU), Nanjing, China.
  • Behmoaras J; Centre for Inflammatory Disease, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK; Centre for Computational Biology and Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore. Electronic address: jacquesb@duke-nus.edu.sg.
EBioMedicine ; 103: 105127, 2024 May.
Article en En | MEDLINE | ID: mdl-38677183
ABSTRACT

BACKGROUND:

Obesity drives maladaptive changes in the white adipose tissue (WAT) which can progressively cause insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated liver disease (MASLD). Obesity-mediated loss of WAT homeostasis can trigger liver steatosis through dysregulated lipid pathways such as those related to polyunsaturated fatty acid (PUFA)-derived oxylipins. However, the exact relationship between oxylipins and metabolic syndrome remains elusive and cross-tissue dynamics of oxylipins are ill-defined.

METHODS:

We quantified PUFA-related oxylipin species in the omental WAT, liver biopsies and plasma of 88 patients undergoing bariatric surgery (female N = 79) and 9 patients (female N = 4) undergoing upper gastrointestinal surgery, using UPLC-MS/MS. We integrated oxylipin abundance with WAT phenotypes (adipogenesis, adipocyte hypertrophy, macrophage infiltration, type I and VI collagen remodelling) and the severity of MASLD (steatosis, inflammation, fibrosis) quantified in each biopsy. The integrative analysis was subjected to (i) adjustment for known risk factors and, (ii) control for potential drug-effects through UPLC-MS/MS analysis of metformin-treated fat explants ex vivo.

FINDINGS:

We reveal a generalized down-regulation of cytochrome P450 (CYP)-derived diols during obesity conserved between the WAT and plasma. Notably, epoxidediol ratio, indicative of soluble epoxide hydrolyse (sEH) activity, increases with WAT inflammation/fibrosis, hepatic steatosis and T2DM. Increased 12,13-EpOMEDiHOME in WAT and liver is a marker of worsening metabolic syndrome in patients with obesity.

INTERPRETATION:

These findings suggest a dampened sEH activity and a possible role of fatty acid diols during metabolic syndrome in major metabolic organs such as WAT and liver. They also have implications in view of the clinical trials based on sEH inhibition for metabolic syndrome.

FUNDING:

Wellcome Trust (PS3431_WMIH); Duke-NUS (Intramural Goh Cardiovascular Research Award (Duke-NUS-GCR/2022/0020); National Medical Research Council (OFLCG22may-0011); National Institute of Environmental Health Sciences (Z01 ES025034); NIHR Imperial Biomedical Research Centre.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tejido Adiposo Blanco / Oxilipinas / Hígado Graso / Obesidad Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tejido Adiposo Blanco / Oxilipinas / Hígado Graso / Obesidad Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Países Bajos