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

Autophagy, a fundamental cellular process, is critically involved in the regulation of lipid metabolism within the liver, positioning it as a significant therapeutic avenue for addressing metabolic dysfunction-associated steatotic liver disease, commonly referred to as MASLD. This research endeavor was undertaken to evaluate the effectiveness of the Tat-Beclin-1 peptide, designated as TB-1, a molecule specifically designed to induce autophagy, in alleviating the features of MASLD.

Initially, our investigation focused on examining the impact of the TB-1 peptide on autophagic activity and the metabolism of lipids within cells. We used HepG2 cells, a human liver cell line, and treated them with oleic acid to mimic lipid accumulation. A Tat scrambled peptide, denoted as TS, served as a control for comparison. Following these in vitro studies, we developed an in vivo model of MASLD by feeding mice a high-fat diet for a period of 16 weeks. Subsequently, these mice were administered either the TB-1 peptide or the TS control peptide via intraperitoneal injection.

Our assessments in these animal models included detailed liver histopathology to examine tissue structure, serum biochemistry to analyze liver function and metabolic parameters, and the analysis of key autophagy markers to determine the extent of autophagic activity. The results of our in vitro experiments demonstrated that the TB-1 peptide significantly increased the ratio of LC3II to β-actin, a well-established marker of autophagy, in a manner that was dependent on both the dose of the peptide administered and the duration of treatment.

Furthermore, TB-1 treatment was found to promote the expression of crucial autophagy-related proteins, namely Beclin-1 and the ATG5-12 conjugate. Notably, TB-1 treatment also led to a substantial reduction in both the size and the number of lipid droplets that had accumulated within the HepG2 cells. In our in vivo studies, mice that were fed a high-fat diet exhibited several characteristics of MASLD, including increased liver weight, elevated levels of alanine aminotransferase in the serum (an indicator of liver damage), and impaired oral glucose tolerance, suggesting metabolic dysfunction.

However, the administration of the TB-1 peptide effectively mitigated these hepatic and metabolic disturbances. Histological examination of the liver tissue further revealed a considerable reduction in the severity of hepatic steatosis, or fatty liver, and fibrosis, or scarring, in the mice treated with TB-1 compared to those that received the TS control peptide.

In conclusion, our findings indicate that the TB-1 peptide demonstrates significant potential in reducing the severity of MASLD in both cellular models using HepG2 cells and in mouse models where MASLD was induced by a high-fat diet. Enhancing the process of autophagy through the use of the TB-1 peptide thus represents a promising therapeutic strategy for the treatment of MASLD.