Mannose reduces fructose metabolism and reverses MASH in human liver slices and murine models in vivo.

BACKGROUND: Fibrosis drives liver-related mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet we have limited medical therapies to target MASH-fibrosis progression. Here we report that mannose, a simple sugar, attenuates MASH steatosis and fibrosis in 2 robust murine models and human liver slices. METHODS: The well-validated fat-and-tumor MASH murine model for liver steatosis and fibrosis was employed. Mannose was supplied in the drinking water at the start ("Prevention" group) or at week 6 of the 12-week MASH regimen ("Therapy" group). The in vivo antifibrotic effects of mannose supplementation were tested in a second model of carbon tetrachloride (CCl4)-induced liver fibrosis. A quantitative and automated digital pathology approach was used to comprehensively assess steatosis and fibrosis phenotypes. Mannose was also tested in vitro in human and primary mouse hepatocytes conditioned with free fatty acids alone or with fructose, and human precision-cut liver slices from patients with end-stage MASH cirrhosis. RESULTS: Oral mannose supplementation improved liver fibrosis in vivo in both fat-and-tumor MASH and CCl4 mouse models, as well as in human precision-cut liver slice MASH samples. Mannose also reduced liver steatosis in fat-and-tumor MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase, the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and human precision-cut liver slices. Removal of fructose or overexpression of ketohexokinase each abrogated the antisteatotic effects of mannose. CONCLUSIONS: This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte ketohexokinase expression and exerts independent antifibrotic effects in 2 mouse models and human liver tissue slices.