Nynke Simons1,2,3, François-Guillaume Debray4, Nicolaas C Schaper1,3,5, M Eline Kooi3,6, Edith J M Feskens7, Carla E M Hollak8, Lucas Lindeboom6,9,10, Ger H Koek9,11,12, Judith A P Bons13, Dirk J Lefeber14,15, Leanne Hodson16, Casper G Schalkwijk2,3, Coen D A Stehouwer2,3,17, David Cassiman18, Martijn C G J Brouwers1,2,3. 1. Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands. 2. Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands. 3. CARIM School for Cardiovascular Diseases, Maastricht, Netherlands. 4. Department of Medical Genetics, Metabolic Unit, University Hospital Liège, Liège, Belgium. 5. School for Public Health and Primary Care (CAPHRI), Maastricht, Netherlands. 6. Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands. 7. Division of Human Nutrition, Wageningen University, Wageningen, Netherlands. 8. Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands. 9. School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands. 10. Department of Nutrition and Movement Sciences, Maastricht University Medical Center, Maastricht, Netherlands. 11. Department of Internal Medicine, Division of Gastroenterology & Hepatology, Maastricht University Medical Center, Maastricht, Netherlands. 12. Department of Surgery, Klinikum, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany. 13. Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands. 14. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands. 15. Department of Neurology, Radboud University Medical Center, Nijmegen, Netherlands. 16. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom. 17. Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands. 18. Department of Gastroenterology-Hepatology and Metabolic Center, University Hospital Leuven, Leuven, Belgium.
Abstract
CONTEXT: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates. OBJECTIVE: To translate these experimental findings to the human situation. DESIGN: Case-control study. SETTING: Outpatient clinic for inborn errors of metabolism. PATIENTS OR OTHER PARTICIPANTS: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). MAIN OUTCOME MEASURE: IHTG content, assessed by proton magnetic resonance spectroscopy. RESULTS: IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009). CONCLUSIONS: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.
CONTEXT: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates. OBJECTIVE: To translate these experimental findings to the human situation. DESIGN: Case-control study. SETTING:Outpatient clinic for inborn errors of metabolism. PATIENTS OR OTHER PARTICIPANTS: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). MAIN OUTCOME MEASURE: IHTG content, assessed by proton magnetic resonance spectroscopy. RESULTS:IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009). CONCLUSIONS: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.
Authors: Nynke Simons; François-Guillaume Debray; Nicolaas C Schaper; Edith J M Feskens; Carla E M Hollak; Judith A P Bons; Jörgen Bierau; Alfons J H M Houben; Casper G Schalkwijk; Coen D A Stehouwer; David Cassiman; Martijn C G J Brouwers Journal: Mol Genet Metab Rep Date: 2020-05-11