Mangiferin modulates lipid metabolism via AKR1B1 in response to advanced glycation end products

Dysregulation of lipid metabolism is a hallmark of diabetic peripheral neuropathy (DPN). We hypothesised that AKR1B1, a gene upregulated under hyperglycaemic conditions in DPN, promotes lipid droplet formation in neuroblastoma cells.

We explored the role of AKR1B1 in lipid metabolism and its regulation by advanced glycation end products (AGEs) using transcriptomic analysis and human neuroblastoma (IMR-32) cell models. We also screened heterocyclic compounds to identify potential AKR1B1 inhibitors, followed by molecular docking, dynamics simulations, and biochemical assays to validate the findings.

Transcriptomic analysis revealed AKR1B1 as a key lipid metabolism regulator in DPN probands. AGE-HSA treatment increased AKR1B1 expression and activity by enhancing OCT1 phosphorylation at serine-385, facilitating OCT1 binding to the AKR1B1 promoter. AGE-HSA also induced lipid droplet formation in a dose- and time-dependent manner, which was further enhanced by AKR1B1 overexpression. Mangiferin was identified as a potent AKR1B1 inhibitor. Molecular modelling showed mangiferin stably binds to AKR1B1's substrate-binding cavity (engaging Y48, H110, W111 residues). Biochemical assays confirmed mangiferin as a competitive inhibitor, effectively reducing AKR1B1 activity and lipid droplet accumulation. Mangiferin also decreased AKR1B1 and DGAT2 levels, counteracting AGE-induced lipid dysregulation while preserving SCD1 expression.

These findings establish AKR1B1 as a critical regulator of lipid metabolism in DPN and identify mangiferin as a promising therapeutic agent to inhibit AKR1B1 activity and restore lipid homeostasis in diabetic neuropathy.