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

Background & Aims: 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 two robust murine models and human liver slices. Methods: The well-validated FAT-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 anti-fibrotic 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 (hPCLS) from patients with end-stage MASH cirrhosis. Results: Oral mannose supplementation improved liver fibrosis in vivo in both FAT-MASH and CCl4 mouse models, as well as in hPCLS MASH samples. Mannose also reduced liver steatosis in FAT-MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase (KHK), the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and hPCLS. Removal of fructose or overexpression of KHK each abrogated the anti-steatotic effects of mannose. Conclusions: This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte KHK expression and exerts independent anti-fibrotic effects in two mouse models and human liver tissue slices. Overall design: RNA-seq profiling of total mouse liver RNA from mice raised for 12 weeks (starting age 8 weeks old, end 20 weeks) on normal chow diet, or high fat/sugar/cholesterol diet with weekly low dose carbon tetrachloride IP injection (FAT-MASH regimen). Treatment groups were without mannose, 5% mannose, or 20% mannose in drinking water (ad libitum) for 12 weeks (Prevention groups), or mannose commencing at 6-weeks on diet (Therapy groups).