20S-O-Glc-DM regulates fatty acid metabolism and mitochondrial function in the treatment of diabetes mellitus-associated MAFLD.

BACKGROUND

The prevalence of diabetes mellitus-associated metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise, with over 90% of patients with Type 2 Diabetes Mellitus (T2DM) also suffering from MAFLD. Currently, there are no specific drugs available for the treatment of diabetes mellitus-associated MAFLD. Ginsenoside is commonly used to treat both MAFLD and diabetes. Previous studies have used biosynthesis to obtain the ginsenoside precursor compound 20S-O-Glc-DM (C20DM), which is suitable for industrial production, has high bioavailability, and is promising as a new treatment option for diabetes mellitus-associated MAFLD.

PURPOSE

This study is the first to reveal the protective effects of C20DM on diabetes mellitus-associated MAFLD and its potential pharmacological mechanisms.

METHODS

We used DB/DB mice fed a high-fat diet as an animal model of diabetes mellitus-associated MAFLD and HepG2 cells treated with high glucose medium combined with oleic acid as an in vitro model. In vivo, eukaryotic transcriptome sequencing and 16S rRNA analysis were used to explore the mechanism of action of C20DM. In vitro, further validation of the relationship between PGC-1α and C20DM in improving diabetes mellitus-associated MAFLD was conducted using the SR18292 inhibitor.

RESULTS

In both the in vitro and in vivo models of diabetes mellitus-associated MAFLD, C20DM improved hepatic lipid accumulation and mitochondrial function. 16S rRNA analysis revealed that C20DM ameliorated gut microbiota dysbiosis and increased the abundance of microbiota associated with mitochondrial function. Eukaryotic transcriptome analysis showed that differentially expressed genes were primarily involved in hepatic fatty acid metabolism and the PPAR pathway, with PGC-1α playing a key role.

CONCLUSIONS

In conclusion, our study demonstrates that C20DM improves diabetes mellitus-associated MAFLD by regulating fatty acid metabolism and mitochondrial function through the PGC-1α/PPARα/CPT1A pathway.