Tat-Beclin-1 Peptide Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Enhancing Hepatic Autophagy.

Abstract

Autophagy plays a crucial role in hepatic lipid metabolism, making it a key therapeutic target for addressing metabolic dysfunction-associated steatotic liver disease (MASLD). This study evaluates the efficacy of the Tat-Beclin-1 (TB-1) peptide, a specific autophagy inducer, in mitigating MASLD. Initially, we examined the impact of the TB-1 peptide on autophagic activity and intracellular lipid metabolism in HepG2 cells treated with oleic acid, using a Tat scrambled (TS) control peptide for comparison. Subsequently, we established a MASLD mouse model by feeding a high-fat diet (HFD) for 16 weeks, followed by intraperitoneal administration of TB-1 or TS. Assessments included liver histopathology, serum biochemistry, and autophagy marker analysis. Our findings indicate that the TB-1 peptide significantly increased the LC3II/β-actin ratio in a dose- and time-dependent manner while promoting the expression of key autophagy markers Beclin-1 and ATG5-12. Furthermore, TB-1 treatment led to a marked reduction in both the size and number of lipid droplets in HepG2 cells. In vivo, HFD-fed mice exhibited increased liver weight, elevated serum alanine aminotransferase levels, and impaired oral glucose tolerance. TB-1 administration effectively mitigated these hepatic and metabolic disturbances. Histological analysis further revealed a substantial reduction in the severity of hepatic steatosis and fibrosis in TB-1-treated mice compared to TS controls. In conclusion, the TB-1 peptide shows significant potential in reducing the severity of MASLD in both HepG2 cell models and HFD-induced MASLD mouse models. Enhancing autophagy through TB-1 represents a promising therapeutic strategy for treating MASLD.