Plasma lipidomics identifies a signature of 1 NAFLD in children that couples with 2 cardiometabolic outcomes in adults . 3 4

61 Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children and adults 62 characterized by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of 63 cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac 64 events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to 65 investigate these perturbations and understand how closely they mimic the changes seen in adults with 66 cardiometabolic disease. We hypothesized that change in the concentration of lipid species in pediatric 67 NAFLD would mimic the alterations known to be associated with CVD in adults (and be largely 68 reflective of insulin resistance). Here, we performed untargeted liquid chromatography mass spectrometry 69 (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 70 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology 71 were assessed using regression adjusted for age and sex. Results were then replicated using data from 72 9,500 adults with metabolic phenotyping. Phosphatidylcholine (PC) and triglyceride (TG) desaturation 73 and chain length were inversely associated with histological severity of paediatric NAFLD. Nine lipids 74 species (lyso-PC, PC, and TG classes) were also associated with hepatic steatosis and insulin resistance in 75 an independent cohort of adults. Five of the 9 lipids replicated in the adults cohort (including PC(36:4)) 76 have been directly linked to death and cardiometabolic disease in adults, as well as indirectly via genetic 77 variants that influence the concentration of these species. Together, these findings suggest that lipid 78 metabolism is altered in paediatric NAFLD in a similar way as in cardiometabolic disease in adults and it 79 is therefore critical to alleviate insulin resistance in these children to mitigate their long-term morbidity. 80 81 82 83 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 17, 2021. ; https://doi.org/10.1101/2020.04.18.20070417 doi: medRxiv preprint