Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria

K. Gianmoena, N. Gasparoni, A. Jashari, P. Gabrys, K. Grgas, A. Ghallab, K. Nordstrom, G. Gasparoni, J. Reinders, K. Edlund, P. Godoy, A. Schriewer, H. Hayen, C.A. Hudert, G. Damm, D. Seehofer, T.S. Weiss, P. Boor, H.J. Anders, M. MotrapuP. Jansen, T.S. Schiergens, M. Falk-Paulsen, P. Rosenstiel, C. Lisowski, E. Salido, R. Marchan, J. Walter, J.G. Hengstler, C. Cadenas*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 hyper methylated, 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.
Original languageEnglish
Article number109526
Number of pages27
JournalCell Reports
Volume36
Issue number8
DOIs
Publication statusPublished - 24 Aug 2021

Keywords

  • FATTY LIVER-DISEASE
  • CHRONIC KIDNEY-DISEASE
  • GENE-EXPRESSION
  • CARDIOVASCULAR-DISEASE
  • PRIMARY HEPATOCYTES
  • GLYCOLATE OXIDASE
  • FACTOR-BINDING
  • MOUSE MODELS
  • WEB-SERVER
  • IN-VITRO

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