Targeting Intestinal Transporter Glut5 to Prevent the High Fructose-Induced Steatotic Liver Disease

Objectives: Over consumption of dietary fructose contributes to the development of metabolic dysfunction associated-steatotic liver disease (MASLD), but the role of fructose transporter in the intestine, glucose transporter 5 (GLUT5), is not clear. We aimed to investigate the role of GLUT5 as a novel therapeutic target for MASLD. Methods: Adult male C57BL/6J mice were fed by different doses of fructose in drinking water for 8 weeks from 4%-25%. The intestinal expression of GLUT5, intestinal and liver histology were measured while gut metagenome and metabolome were evaluated. The intestinal-specific Glut5 knock out mice Glut5flox/flox Vil1-Cre ki/wt (Glut5-/-) were built and fed by high fructose alone (HF) or combined with high fat diet (HFF) for 8 weeks to confirm the role of Glut5. Furthermore, we fed 5,6,7-Trimethoxyflavone (TMF), a natural product identified as GLUT5 transporter inhibitor, to wide type (WT) mice to validate its prevention effect on high fructose-induced liver injury. Results: The intestinal GLUT5 expression was significantly increased in WT mice fed by HF for 8 weeks, which developed gut dysbiosis, impaired liver function, and metabolic abnormalities. Compared with WT mice, after feeding HF or HFF diet for 8 weeks, the intestinal and liver damage were alleviated in Glut5-/- mice. Moreover, we confirmed that the natural product, TMF, could effectively inhibited the intestinal expression of GLUT5 and improved the development of MASLD in WT mice. Conclusions: The intestinal GLUT5 is a potential therapeutic target to alleviate the high fructose-induced MASLD and the natural product of GLUT5 inhibitor-TMF can be a promising candidate for MASLD prevention and intervention. Funding Sources: This work was funded by the National Natural Science Foundation of China (82170583, 81900510).