Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis

Background & Aims: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasises lifestyle interventions, but few patients adhere to such strategies. New targeted therapies are urgently required. Methods: We have used a unique combination of human liver specimens, a murine dietary model of NAFLD and human multicellular co-culture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed nuclear magnetic resonance-based metabolic tracing of the fate of isotopically labelled fructose upon administration to the human liver. Results: Expression of KHK isoforms is found in multiple human hepatic cell types, although hepatocyte expression predominates. KHK knockout mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on an Amylin diet. Human co-cultures exposed to fructose exhibit steatosis and activation of lipogenic and fibrogenic gene expression, which were reduced by pharmacological inhibition of KHK activity. Analysis of human livers exposed to 13C-labelled fructose confirmed that steatosis, and associated effects, resulted from the accumulation of lipogenic precursors (such as glycerol) and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of a KHK inhibitor. Conclusions: We have provided preclinical evidence using human livers to support the use of KHK inhibition to improve steatosis, fibrosis, and inflammation in the context of NAFLD. Lay summary: We have used a mouse model, human cells, and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future

Does larger tumor volume explain the higher prostate specific antigen levels in black men with prostate cancer—Results from the SEARCH database

OBJECTIVES: To assess whether larger tumor volume in black men explains higher presurgical PSA levels versus white men with prostate cancer. METHODS: We retrospectively analyzed 1904 men from the Shared Equal Access Regional Cancer Hospital database who underwent radical prostatectomy from 1990 to 2013. Geometric mean of tumor volume and preoperative PSA for each race were estimated from multivariable linear regression models. RESULTS: There were 1104 (58%) white men and 800 (42%) black men. Black men were younger (60.2 vs. 62.9years, p<0.001) had a higher PSA (6.7 vs. 6.0ng/mL, p<0.001), more positive margins (47 vs. 38%, p<0.001), and seminal vesicle invasion (13 vs. 9%, p=0.007). White patients had higher clinical stage (p<0.001) and greater median tumor volume (6.0 vs. 5.3gm, p=0.011). After multivariable adjustment (except for PSA), white men had smaller mean tumor volumes (5.2 vs. 5.8gm, p=0.011). When further adjusted for PSA, there was no racial difference in mean tumor volume (p=0.34). After multivariable adjustment, black men had higher mean PSAs vs. white men (7.5 vs. 6.1ng/mL, p<0.001). Results were similar after further adjusting for tumor volume: black men had 16% higher mean PSAs versus white men (7.4 vs. 6.2ng/mL, p<0.001). CONCLUSIONS: In this study of men undergoing radical prostatectomy at multiple equal access medical centers, racial differences in tumor volume did not explain higher presurgical PSA levels in black versus white men. The exact reason for higher PSA values in black men remains unclear