Role of ALDH18A1 in regulating the progression of Metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) continues to be a considerable health problem. We identify Aldehyde dehydrogenase 18 family, member A1 (ALDH18A1) as a key factor in MASH aggravation via promoting liver proline accumulation. Silencing of the liver-specific Aldh18a1 gene mitigates MASH, while overexpression of ALDH18A1 exacerbates the phenotype of MASH. Mechanistically, under MASH pathological conditions, ALDH18A1 may affect hepatic lipid metabolism through increasing proline synthesis in hepatocytes. Our results indicate that the overexpression of the enzyme-inactive mutant of ALDH18A1 at the cellular level does not promote lipid accumulation in hepatocytes, in contrast to the overexpression of the wild-type ALDH18A1. Moreover, our observations of inhibited cellular mitochondrial respiratory function due to ALDH18A1 overexpression demonstrated that the overexpression of ALDH18A1, which drives higher proline concentration, is associated with impaired mitochondrial respiratory function. The results indicate that the suppression of hepatic proline production may be beneficial for the advancement of new MASH therapeutics.