TNAP dephosphorylates phosphocholine and phosphoethanolamine and participates in triglyceride transport from the liver to the bloodstream
Tissue-nonspecific alkaline phosphatase (TNAP) is primarily known for its role in skeletal mineralization, through the hydrolysis of inorganic pyrophosphate (PP<sub>i</sub>). Here we demonstrate that TNAP-knockout mice exhibit liver steatosis and reduced serum triglyceride levels, mirroring the effects of choline deficiency, which impairs phosphatidylcholine synthesis, an essential component of VLDL. In fasting WT mice, TNAP inhibition via SBI-425 administration decreases choline levels in blood and liver. Incubating mouse or human serum with SBI-425 inhibits the dephosphorylation of phosphocholine and phosphoethanolamine, an alternative substrate for hepatic phosphatidylcholine synthesis. In hepatocytes, TNAP inhibition impedes proliferation when the medium is supplemented with phosphocholine instead of choline. Recombinant TNAP hydrolyzes phosphocholine and phosphoethanolamine with similar efficiency than PP<sub>i</sub>. X-ray diffraction and cryo-EM identified the residues in TNAP's active site interacting with phosphocholine, PP<sub>i</sub> and the TNAP inhibitor. In summary, TNAP is the phosphatase enabling cellular choline uptake during fasting, participating in hepatic lipid metabolism.
Authors
- Lionel Ballut (ORCID: https://orcid.org/0000-0002-3982-9321)
- Anne Briolay
- Sébastien Violot (ORCID: https://orcid.org/0000-0001-7749-9207)
- Véronique Gilard (ORCID: https://orcid.org/0000-0002-8379-8091)
- Stéphane Balayssac (ORCID: https://orcid.org/0000-0001-7349-3959)
- José Luís Millán (ORCID: https://orcid.org/0000-0002-1547-2671)
- Gilles J. P. Rautureau (ORCID: https://orcid.org/0000-0002-1064-0293)
- Sonoko Narisawa
- Eva Drevet Mulard (ORCID: https://orcid.org/0000-0002-3925-4097)
- Laurence Bessueille (ORCID: https://orcid.org/0000-0003-4692-8077)
- David Magne (ORCID: https://orcid.org/0000-0002-6511-9390)
- Pierre‐Damien Coureux (ORCID: https://orcid.org/0000-0002-1328-7229)
- Iliass Imam (ORCID: https://orcid.org/0009-0004-2098-0752)
- Antoine Tarby
- Felix Lecornu (ORCID: https://orcid.org/0009-0005-7248-4635)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Lyon College (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Structural and Molecular Basis of Infectious Systems (FR)
- Physiopathologie, diagnostic et traitements des maladies musculo-squelettiques (FR)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1038/s42003-025-08901-3
- Citations
- 1
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.32
Funders
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- French Infrastructure for Integrated Structural Biology
- European Research Area Network on Cardiovascular Diseases
- National Institutes of Health