Lipidomics Uncovers Metabolic Manifestations Related to Liver Steatosis and Low-Grade Systemic Inflammation in Diet-Treated Hereditary Fructose Intolerance Patients

Abstract

Background and Aims Hereditary Fructose Intolerance (HFI), a rare autosomal recessive metabolic disorder, has historically been considered benign when treated with a lifelong fructose-, sucrose and sorbitol-restricted diet. However, adverse metabolic manifestations have recently been reported in treated HFI patients. As serum metabolomics offers a valuable tool for assessing metabolic manifestations underlying inherited metabolic disorders, we aim to compare the serum lipidomic profile of HFI-treated patients with age-, gender-, and body mass index-matched healthy controls. Methods Long-term dietary-treated HFI patients (n=32) were compared to age-, sex-, and BMI-matched healthy controls (n=28) using serum lipidomic analysis by tandem mass spectrometry, followed by pathway enrichment analysis. Furthermore, liver magnetic resonance imaging/spectroscopy (MRI/MRS), plasma lipoprotein and glycoprotein profiling using the LiposcaleⓇ, a two-dimensional proton nuclear magnetic resonance (2D-1H-NMR) spectroscopy test, sialotransferrin analysis, and serum multiplex analysis of cytokines/chemokines were performed. Results The HFI patients exhibited a distinct serum lipidomic profile showing separate clusters in the multivariate analysis between these patients and the healthy controls. Top-interacting network analysis revealed abnormalities in lipid metabolism and inflammation as hallmarks of HFI. Indeed, significant liver steatosis, assessed by MRS proton density fat fraction (MRS-PDFF), was present in 75% of HFI patients compared to 7% in the control group. Moreover, low-grade systemic inflammation was highly prevalent in HFI patients, exhibiting elevated serum cytokines, C-reactive protein, acute phase proteins such as fibrinogen and ferritin, and increased low-grade inflammation score. Additionally, circulating glycoprotein acetyls (GlycA), a novel serum marker for low-grade inflammation, was significantly elevated in the HFI patients and associated with their lipidomic profile and markers of altered intestinal permeability, such as serum lipopolysaccharide binding protein. Furthermore, increased GlycA concentration in the HFI patients was associated with elevation of blood pressure and an altered serum lipoprotein profile, early factors of cardiovascular risk. Conclusions Serum lipidomic study revealed previously unknown metabolic complications of HFI-treated patients. Notably, we have found that low-grade systemic inflammation is highly prevalent in the cohort of HFI patients and correlates with early factors of cardiovascular risk. Expanding our current understanding of the metabolic consequences in HFI-treated patients will provide the best care for patients.