Vitamin K2 Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease Through Mitochondrial Dysfunction...

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. Meanwhile, the development of MASLD is related to dysbiosis of the gut microbiota (GM). Our previous studies have shown that Vitamin K2 (VK2) has considerable potential to ameliorate mitochondrial dysfunction in mice fed a high-fat diet (HFD); however, the mechanism through which VK2 improves mitochondrial function and mitigates MASLD remains unclear.

This study aimed to elucidate the mechanism through which VK2 modulates MASLD.

A total of 80 C57BL/6J mice (4-5 weeks old) were fed a HFD for 16 weeks to establish the MASLD animal model. Additionally, VK2 was administered at a dose of 120 mg/kg/day for the last 8 weeks; 30 mice were fed a normal diet for the entire 24-week period. Mice were randomly divided into groups according to different experimental protocols. Hematoxylin and Eosin (H&E) staining, Oil Red O staining, and Cluster of Differentiation 11b (CD11b) immunofluorescence staining were used to detect liver histology and inflammatory cell infiltration in the mouse liver tissues. Moreover, 16S rRNA gene sequencing, antibiotic treatment, and fecal microbiota transplantation (FMT) were employed to investigate the microbiota-mediated anti-MASLD effects of VK2. Adeno-associated virus 9 (AAV9) was used to elucidate the mechanism through which VK2 regulates MASLD severity.

VK2 significantly reduced hepatic lipid (triacylglycerol (TG) and total cholesterol (TC)) levels, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in HFD-fed mice (p < 0.05). VK2 also significantly suppressed inflammatory responses (p < 0.05), oxidative stress (p < 0.05), and improved mitochondrial dysfunction (p < 0.05) in a GM-dependent manner. Furthermore, VK2 restored the balance in the intestinal microbiota primarily through regulating Lactobacillus spp. abundance, and markedly alleviated MASLD via a GM-dependent manner. VK2 notably upregulated the expression of SIRT3 signaling pathway proteins (p < 0.05), thereby reducing MASLD-associated mitochondrial dysfunction (p < 0.05).

VK2 exerts promising therapeutic effects mainly through enhancing intestinal Lactobacillus abundance and ameliorating mitochondrial dysfunction.