Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver disorders worldwide. However, its molecular drivers of progression are not clearly defined.

A new study published in Life Medicine on January 20 identified the metabolic enzyme SIRT5 as a critical suppressor of MASLD progression that reshapes hepatic metabolic pathways. 

The work was led by researchers from the Institute of Biophysics of the Chinese Academy of Sciences, Beijing Tsinghua Changgung Hospital, and Chinese Academy of Medical Sciences & Peking Union Medical College.

Using dietary mouse models of MASLD, the researchers observed that Sirt5-deficient mice developed more severe steatosis and liver injury compared to controls. Histological analyses revealed increased lipid deposition and collagen staining, indicating heightened fibrotic remodeling.

To uncover the metabolic mechanisms underlying these phenotypes, the researchers performed multi-omics profiling, including transcriptomic, metabolomic, and proteomic analyses. These datasets collectively showed that SIRT5 regulates pathways linked to central carbon metabolism, amino acid catabolism, and redox homeostasis.

In Sirt5-deficient livers, the dysregulation of these pathways resulted in increased oxidative stress and inflammatory signaling, thereby promoting tissue damage and disease progression.

This study demonstrates the protective role of SIRT5 against metabolic dysregulation and chronic inflammation during MASLD progression. In MASLD mouse models, elevated free fatty acids and pro-inflammatory cytokines induced the expression of the E3 ubiquitin ligase TRIM21, which drove SIRT5 degradation.

Reduced SIRT5 levels resulted in increased lysine succinylation and malonylation of multiple metabolism-related and inflammation-associated proteins, which impaired their function. Restoring SIRT5 expression eliminated excessive protein acylation, improved glucose and lipid metabolism, and attenuated chronic inflammatory responses.

Overall, these findings reveal that metabolic rewiring plays a critical role in the development of liver disease and identify SIRT5 as a protective factor against MASLD. By linking hepatic metabolism to inflammatory and fibrotic responses, the study establishes a foundation for future therapeutic intervention strategies.

SIRT5 alleviates metabolic abnormalities and chronic inflammation in MASLD mice (Image by WEI Taotao's group)