Journal
BIOTECHNOLOGY AND BIOENGINEERING
Volume 118, Issue 11, Pages 4331-4337Publisher
WILEY
DOI: 10.1002/bit.27901
Keywords
ammonia; aquaporin-8; hepatocytes; mitochondria; ureagenesis
Categories
Funding
- Consejo Nacional de Investigaciones Cientificas y Tecnicas [PIP 2015-088, PUE 0089]
- Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2018-02643]
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The study demonstrates that adenoviral gene transfer of human AQP8 to hepatocyte mitochondria enhances ammonia conversion to urea, leading to significantly increased urea synthesis and improved ammonia detoxification in liver cells. This finding indicates the potential therapeutic implications for liver diseases with impaired ammonia detoxification.
Hepatic ammonia detoxification to urea is critical for the prevention of hyperammonemia and neurological damage. Hepatocyte mitochondrial aquaporin-8 (AQP8) channels have been involved in ammonia-derived ureagenesis. Herein, we studied whether the adenoviral gene transfer of human AQP8 (hAQP8) to hepatocyte mitochondria enhances ammonia conversion to urea. Using primary cultured rat hepatocytes, we first confirmed the mitochondrial expression of hAQP8 and then, using unlabeled or N-15-labeled ammonia, we demonstrated that the urea synthesis was significantly enhanced in hAQP8-transduced hepatocytes. Studies using isolated hAQP8-expressing mitochondria also showed an increased ammonia metabolism. hAQP8 transduction was able to recover the impaired ammonia-derived ureagenesis in hepatotoxin-treated hepatocytes. Our data suggest that mitochondrially-expressed hAQP8 enhances and improves hepatocyte ammonia conversion to urea, a finding with potential therapeutic implications for liver disease with impaired ammonia detoxification.
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