The role of tryptophan hydroxylase-1 in metabolic dysfunction-associated steatotic liver disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by dysregulated lipid metabolism, inflammation, and mitochondrial dysfunction. Given the rising burden of MASLD in children and adolescents, identifying experimentally tractable mechanisms relevant to pediatric diseases is of considerable interest. Tryptophan hydroxylase-1 (TPH1), the rate-limiting enzyme for peripheral serotonin synthesis, has been implicated in metabolic disorders, but its hepatic role in MASLD remains unclear. Objective: To investigate whether Methods: MASLD was induced in young adult male C57BL/6J mice by a 12-week high-fat diet (HFD). At HFD onset, mice received a single tail-vein injection of liver-tropic AAV8-shTph1 or the control AAV8. The HFD feeding was continued for 12 weeks until the end of the experiment. Hepatic histology, serum biochemistry, oxidative stress, inflammatory responses, apoptosis, and mitochondrial function were also evaluated. Mechanistic studies were conducted in palmitic acid/oleic acid-treated AML12 hepatocytes using siRNA targeting Results: Hepatic TPH1 expression was elevated in MASLD mice. Interpretation: Hepatic TPH1 is associated with MASLD progression and impaired Parkin-mediated mitophagy.