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

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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Figure 5

CF kidney exhibits defective amino acid reabsorption.

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CF kidney exhibits defective amino acid reabsorption. (A) Schematic of r...
(A) Schematic of renal filtration and reabsorption. Most metabolites are first filtered, and selected metabolites are then actively reabsorbed back into the systemic circulation. (B) Heatmap showing 28 metabolite abundance ratios of the renal vein relative to the artery and urine relative to the artery. Blue color in urine/artery indicates reabsorption, and red color indicates loss into urine. *P < 0.05, **P < 0.01, and ***P < 0.001 of CF urine/artery relative to WT, by 2-tailed Student’s t test or Mann-Whitney U test (see Supplemental Table 2). Urine data were normalized to urine creatinine levels. (C) Correlation between WT urine/artery and CF urine/artery for each circulating metabolite (color coded by categories). Examples of amino acids that are poorly reabsorbed in CF are labeled. (D) Schematic of stable isotope tracing in pigs. Pigs were intravenously infused with four 13C-labeled amino acid tracers. (E) 13C-labeled amino acid abundance in WT and CF urine samples. The ion counts of 13C-labeled amino acids in urine (normalized to urine creatinine) were normalized to the labeled amino acids in arterial blood. Data are individual points with the mean shown by a blue line. n = 2 WT and n = 2 CF littermates. (F) Fold difference in urine amino acids, normalized by urine osmolality, from 12-month-old children with CF (n = 22) relative to non-CF controls (n = 22). P values by Welch’s 2-sample t test. Data were adapted from BONUS (12).