The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPARα

The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid regulatory activity of PPARα.In healthy hepatocytes, the transcriptional activity of Peroxisome Proliferator-Activated Receptor α (PPARα) is activated upon fasting by its natural ligands (i.e.fatty acids (FA)) or upon treatment by its synthetic agonist.In response, PPARα activates the transcription of FA oxidation-related genes, hence stimulating lipid metabolism.In Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD), the ubiquitin-like modifier protein human leukocyte antigen-F Adjacent Transcript 10 (FAT10) is induced by pro-inflammatory stimuli (i.e.Interferon γ (IFNγ), Interleukin 6 (IL6) and Tumor Necrosis Factor α (TNFα)).FAT10 then interacts with PPARα, resulting in the inhibition of PPARα activation by its ligands.As a consequence, lipid metabolism and FA oxidation are impaired, and the accumulation of lipid droplets, steatosis and MASLD progression promoted.