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

Background and aims: Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) is a key regulator of hepatic lipid metabolism and therefore a promising therapeutic target against Metabolic-dysfunction Associated Steatotic Liver Diseases (MASLD). However, its expression and activity decrease during disease progression and several of its agonists did not achieve sufficient efficiency in clinical trials with, surprisingly, a lack of steatosis improvement. Here, we identified the Human leukocyte antigen-F Adjacent Transcript 10 (FAT10) as an inhibitor of PPAR alpha lipid metabolic activity during MASLD progression.Approach and results: In vivo, the expression of FAT10 is upregulated in human and murine MASLD livers upon disease progression and correlates negatively with PPAR alpha expression. The increase of FAT10 occurs in hepatocytes in which both proteins interact. FAT10 silencing in vitro in hepatocytes increases PPAR alpha target gene expression, promotes fatty acid oxidation and decreases intra-cellular lipid droplet content. In line, FAT10 overexpression in hepatocytes in vivo inhibits the lipid regulatory activity of PPAR alpha in response to fasting and agonist treatment in conditions of physiological and pathological hepatic lipid overload.Conclusions: FAT10 is induced during MASLD development and interacts with PPAR alpha resulting in a decreased lipid metabolic response of PPAR alpha to fasting or agonist treatment. Inhibition of the FAT10-PPAR alpha interaction may provide a means to design potential therapeutic strategies against MASLD.