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

Journal volume & issue
Vol. 36, no. 8
p. 109526

Abstract

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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.

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