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Arteriovenous metabolomics in pigs reveals CFTR regulation of metabolism in multiple organs
Hosung Bae, … , Cholsoon Jang, Michael J. Welsh
Hosung Bae, … , Cholsoon Jang, Michael J. Welsh
Published May 14, 2024
Citation Information: J Clin Invest. 2024;134(13):e174500. https://doi.org/10.1172/JCI174500.
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Research Article Metabolism

Arteriovenous metabolomics in pigs reveals CFTR regulation of metabolism in multiple organs

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Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disruption of lung uptake of fatty acids, yet enhancement of uptake of arachidonic acid, a precursor of proinflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multiorgan metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.

Authors

Hosung Bae, Bo Ram Kim, Sunhee Jung, Johnny Le, Dana van der Heide, Wenjie Yu, Sang Hee Park, Brieanna M. Hilkin, Nicholas D. Gansemer, Linda S. Powers, Taekyung Kang, David K. Meyerholz, Victor L. Schuster, Cholsoon Jang, Michael J. Welsh

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