Pivotal role of inter-organ aspartate metabolism for treatment of mitochondrial aspartate-glutamate carrier 2 (citrin) deficiency, based on the mouse model View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-12

AUTHORS

Takeyori Saheki, Mitsuaki Moriyama, Eishi Kuroda, Aki Funahashi, Izumi Yasuda, Yoshiko Setogawa, Qinghua Gao, Miharu Ushikai, Sumie Furuie, Ken-ichi Yamamura, Katsura Takano, Yoichi Nakamura, Kazuhiro Eto, Takashi Kadowaki, David S. Sinasac, Tatsuhiko Furukawa, Masahisa Horiuchi, Yen How Tai

ABSTRACT

Previous studies using citrin/mitochondrial glycerol-3-phosphate (G3P) dehydrogenase (mGPD) double-knockout mice have demonstrated that increased dietary protein reduces the extent of carbohydrate-induced hyperammonemia observed in these mice. This study aimed to further elucidate the mechanisms of this effect. Specific amino acids were initially found to decrease hepatic G3P, or increase aspartate or citrulline levels, in mGPD-knockout mice administered ethanol. Unexpectedly, oral glycine increased ammonia in addition to lowering G3P and increasing citrulline. Subsequently, simultaneous glycine-plus-sucrose (Gly + Suc) administration led to a more severe hyperammonemic state in double-KO mice compared to sucrose alone. Oral arginine, ornithine, aspartate, alanine, glutamate and medium-chain triglycerides all lowered blood ammonia following Gly + Suc administration, with combinations of ornithine-plus-aspartate (Orn + Asp) or ornithine-plus-alanine (Orn + Ala) suppressing levels similar to wild-type. Liver perfusion and portal vein-arterial amino acid differences suggest that oral aspartate, similar to alanine, likely activated ureagenesis from ammonia and lowered the cytosolic NADH/NAD+ ratio through conversion to alanine in the small intestine. In conclusion, Gly + Suc administration induces a more severe hyperammonemic state in double-KO mice that Orn + Asp or Orn + Ala both effectively suppress. Aspartate-to-alanine conversion in the small intestine allows for effective oral administration of either, demonstrating a pivotal role of inter-organ aspartate metabolism for the treatment of citrin deficiency. More... »

PAGES

4179

Journal

TITLE

Scientific Reports

ISSUE

1

VOLUME

9

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-39627-y

DOI

http://dx.doi.org/10.1038/s41598-019-39627-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112706461

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30862943


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