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 Inhibition of 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.
