Multi-tissue pro fi ling of oxylipins reveal a conserved up-regulation of epoxide:diol ratio that associates with white adipose tissue in fl ammation and liver steatosis in obesity

Identifier:  imarina:9369674

Handle: https://hdl.handle.net/20.500.11797/imarina9369674

Authors:  Hateley, Charlotte; Olona, Antoni; Halliday, Laura; Edin, Matthew L; Ko, Jeong-Hun; Forlano, Roberta; Terra, Ximena; Lih, Fred B; Beltran-Debon, Raul; Manousou, Penelopi; Purkayastha, Sanjay; Moorthy, Krishna; Thursz, Mark R; Zhang, Guodong; Goldin, Robert D; Zeldin, Darryl C; Petretto, Enrico; Behmoaras, Jacques

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-de fi ned. Methods We quanti fi ed 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 in fi ltration, type I and VI collagen remodelling) and the severity of MASLD (steatosis, in fl ammation, fi brosis) quanti fi ed 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, epoxide:diol ratio, indicative of soluble epoxide hydrolyse (sEH) activity, increases with WAT in fl ammation/ fi brosis, hepatic steatosis and T2DM. Increased 12,13-EpOME:DiHOME in WAT and liver is a marker of worsening metabolic syndrome in patients with obesity. Interpretation These fi ndings 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.