Role of ketohexokinase in fructose-induced insulin resistance and endothelial dysfunction

Introduction: Fatty liver-associated cardiovascular disease (CVD) is a major cause of mortality. High fat diets (HFD) induce obesity, insulin resistance, diabetes and non-alcoholic fatty liver disease (NAFLD). Adding dietary sugar (HFSD) exacerbates these effects, producing the more severe non-alcoholic steatohepatitis (NASH). Deletion of the gene encoding fructokinase (ketohexokinase, KHK) protects mice from HFSD-induced NASH. The cardiovascular consequences of this protective effect remain incompletely defined; this project aimed to evaluate the sugar-induced metabolic changes accompanying progression of fatty liver to CVD. Methods:NAFLD and NASH were induced by feeding C57/BL6 (WT) mice HFD or HFSD for 20 weeks. The same diets were fed to KHK knockout (KO) animals. Glucose and insulin tolerance tests and whole-body energy measurements were performed at suitable time-points. Endothelial function was studied by measuring isometric tensions in organ bath systems, to gain insights into the progression of NAFLD to CVD. Results: HFD- and HFSD-fed WT developed glucose intolerance, insulin resistance, decreased energy expenditure and endothelial dysfunction. HFSD induced worse parameters than HFD and exerted differential temporal effects on glucose intolerance and insulin resistance, perhaps reflecting the potential for HFSD to exacerbate fatty liver and endothelial dysfunction. The KHK KO mice were protected, not only from HFSD-induced but also some HFD-induced effects, including increased liver weight, fasting hyperglycaemia and hyperinsulinaemia, impaired whole-body energy expenditure and endothelial function. Notably, KO mice were protected from sugar-induced adiposity and random hyperinsulinaemia, but not from the same abnormalities induced by HFD. Conclusions: Although multiple metabolic factors were impaired in both HFD- and HFSD-fed mice, the exacerbated effects of HFSD underscore the additional impact of dietary sugar. A novel finding is that KHK ablation protects not only against HFSD-induced but also HFD-induced pathologies. The results suggest that inhibiting KHK could ameliorate fatty liver and cardiovascular diseases induced by high calorie diets.