Targeting intestinal transporter GLUT5 to alleviate the high-fructose-induced steatotic liver disease.

Excessive dietary fructose consumption is a significant contributor to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role of the intestinal fructose transporter, glucose transporter 5 (GLUT5), in this process remains poorly understood. This study aimed to investigate the potential use of GLUT5 as a novel therapeutic target for MASLD. Eight-week-old male C57BL/6J wild-type (WT) mice were fed a high-fat diet (HFD) or a high-fat diet supplemented with 10% or 25% fructose in drinking water (HFF) for 8 weeks to investigate the effects of high-fructose intake on MASLD development. To further elucidate the role of GLUT5, we utilized an intestine-specific GLUT5 knockout (Slc2a5-IKO) mouse model with HFF diet intervention to evaluate the protective effects of GLUT5 inhibition against high-fructose-induced liver injury. Additionally, the GLUT5 transporter inhibitor, 2,5-anhydro-D-mannitol (2,5-AM), was administered to HFF-fed WT mice to validate the alleviating effect on MASLD. The intestinal expression of GLUT5, liver and intestinal histology, and serum biochemical parameters were analyzed. Intestinal GLUT5 expression was significantly upregulated in WT mice fed HFF for 8 weeks, which developed impaired liver function and metabolic abnormalities. Compared with WT mice, liver damage was significantly attenuated in Slc2a5-IKO mice with the 8-week HFF diet plan. Furthermore, we demonstrated that the GLUT5 inhibitor, 2,5-AM, effectively suppressed intestinal GLUT5 expression and ameliorated the progression of MASLD in WT mice. Intestinal GLUT5 represents a potential therapeutic target for mitigating high-fructose-induced MASLD.