Impaired hepatic metabolism in Hereditary Fructose Intolerance confers fructose-independent risk for steatosis and hypertriglyceridemia.

OBJECTIVES: Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease. METHODS: Aldob was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs. RESULTS: Deletion of Aldob caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI. CONCLUSIONS: Aldob deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.