Cell Reports (Aug 2021)
Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria
- Kathrin Gianmoena,
- Nina Gasparoni,
- Adelina Jashari,
- Philipp Gabrys,
- Katharina Grgas,
- Ahmed Ghallab,
- Karl Nordström,
- Gilles Gasparoni,
- Jörg Reinders,
- Karolina Edlund,
- Patricio Godoy,
- Alexander Schriewer,
- Heiko Hayen,
- Christian A. Hudert,
- Georg Damm,
- Daniel Seehofer,
- Thomas S. Weiss,
- Peter Boor,
- Hans-Joachim Anders,
- Manga Motrapu,
- Peter Jansen,
- Tobias S. Schiergens,
- Maren Falk-Paulsen,
- Philip Rosenstiel,
- Clivia Lisowski,
- Eduardo Salido,
- Rosemarie Marchan,
- Jörn Walter,
- Jan G. Hengstler,
- Cristina Cadenas
Affiliations
- Kathrin Gianmoena
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Nina Gasparoni
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
- Adelina Jashari
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Philipp Gabrys
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Katharina Grgas
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Ahmed Ghallab
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany; Department of Forensic and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
- Karl Nordström
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
- Gilles Gasparoni
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
- Jörg Reinders
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Karolina Edlund
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Patricio Godoy
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Alexander Schriewer
- Department of Analytical Chemistry, Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany
- Heiko Hayen
- Department of Analytical Chemistry, Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany
- Christian A. Hudert
- Department of Pediatric Gastroenterology, Hepatology and Metabolic Diseases, Charité-University Medicine Berlin, 13353 Berlin, Germany
- Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
- Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany; Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
- Thomas S. Weiss
- University Children Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany
- Peter Boor
- Institute of Pathology and Department of Nephrology, University Clinic of RWTH Aachen, 52074 Aachen, Germany
- Hans-Joachim Anders
- Department of Medicine IV, Renal Division, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
- Manga Motrapu
- Department of Medicine IV, Renal Division, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
- Peter Jansen
- Maastricht Centre for Systems Biology, University of Maastricht, 6229 Maastricht, the Netherlands
- Tobias S. Schiergens
- Biobank of the Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
- Maren Falk-Paulsen
- Institute of Clinical Molecular Biology (IKMB), Kiel University and University Hospital Schleswig Holstein, Campus Kiel, 24105 Kiel, Germany
- Philip Rosenstiel
- Institute of Clinical Molecular Biology (IKMB), Kiel University and University Hospital Schleswig Holstein, Campus Kiel, 24105 Kiel, Germany
- Clivia Lisowski
- Institute of Experimental Immunology, University Hospital Bonn, Rheinische-Friedrich-Wilhelms University Bonn, 53127 Bonn, Germany
- Eduardo Salido
- Hospital Universitario de Canarias, Universidad La Laguna, CIBERER, 38320 Tenerife, Spain
- Rosemarie Marchan
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Jörn Walter
- Department of Genetics, Saarland University, 66123 Saarbrücken, Germany
- Jan G. Hengstler
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany
- Cristina Cadenas
- Department of Toxicology, Leibniz-Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), 44139 Dortmund, Germany; Corresponding author
- Journal volume & issue
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Vol. 36,
no. 8
p. 109526
Abstract
Summary: Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release—a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.
