Gianmoena, Kathrin and Gasparoni, Nina and Jashari, Adelina and Gabrys, Philipp and Grgas, Katharina and Ghallab, Ahmed and Nordstroem, Karl and Gasparoni, Gilles and Reinders, Joerg and Edlund, Karolina and Godoy, Patricio and Schriewer, Alexander and Hayen, Heiko and Hudert, Christian A. and Damm, Georg and Seehofer, Daniel and Weiss, Thomas S. and Boor, Peter and Anders, Hans-Joachim and Motrapu, Manga and Jansen, Peter and Schiergens, Tobias S. and Falk-Paulsen, Maren and Rosenstiel, Philip and Lisowski, Clivia and Salido, Eduardo and Marchan, Rosemarie and Walter, Joern and Hengstler, Jan G. and Cadenas, Cristina (2021) Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria. CELL REPORTS, 36 (8): 109526. ISSN 2211-1247,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FATTY LIVER-DISEASE; CHRONIC KIDNEY-DISEASE; GENE-EXPRESSION; CARDIOVASCULAR-DISEASE; PRIMARY HEPATOCYTES; GLYCOLATE OXIDASE; FACTOR-BINDING; MOUSE MODELS; WEB-SERVER; IN-VITRO; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 13:46 |
| Last Modified: | 27 Sep 2022 13:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48109 |
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