Intestinal Depletion of TM6SF2 Exacerbates High-fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease through the Gut-liver Axis.

BACKGROUND AND AIMS

Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common form of chronic liver disease worldwide. This study aimed to explore the role of TM6SF2 in high-fat diet (HFD)-induced MASLD through the gut-liver axis.

METHODS

The TM6SF2 gut-specific knockout (TM6SF2 GKO) mouse was constructed using CRISPR/Cas9 technology. TM6SF2 GKO and wild-type (CON) mice were fed either a HFD or a control diet for 16 weeks to induce MASLD. Blood, liver, and intestinal lipid content, as well as gut microbiota and serum metabolites, were then analyzed.

RESULTS

TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice. The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice. The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase, alanineaminotransferase, and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice, while triglyceride levels were lower. Serum metabolite analysis revealed that HFD-fed TM6SF2 GKO mice had an increase in the expression of 17 metabolites (e.g., LPC [18:0/0-0]) and a decrease in 22 metabolites (e.g., benzene sulfate). The differential metabolites of LPC (18:0/0-0) may serve as HFD-fed TM6SF2 serum biomarkers, leading to MASLD exacerbation in GKO mice.

CONCLUSIONS

TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice. TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.