정선희 (University of California Irvine)

한빛사논문

조회267

University of California Irvine

J. Clin. Invest., May 14 2024, e174500 | https://www.jci.org/articles/view/174500 Arteriovenous metabolomics in pigs reveals CFTR regulation of metabolism in multiple organs

Hosung Bae^1,*, Bo Ram Kim^2,3*, Sunhee Jung^1,*, Johnny Le¹, Dana van der Heide⁴, Wenjie Yu^2,3, Sang Hee Park¹, Brie M. Hilkin², Nicholas D. Gansemer², Linda S. Powers², Taekyung Kang¹, David K. Meyerholz⁵, Victor L. Schuster⁶, Cholsoon Jang^1,7,8,#, Michael J. Welsh^2,3,9,#

¹Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.

²Department of Internal Medicine, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

³Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, USA.

⁴Department of Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

⁵Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

⁶Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

⁷Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA.

⁸Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA.

⁹Department of Molecular Physiology and Biophysics, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA.

^*Equal contributions

^#Correspondence: Cholsoon Jang

Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits 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 are 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 disrupted lung uptake of fatty acids yet enhanced uptake of arachidonic acid, a precursor of pro-inflammatory 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 multi-organ 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.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-16)
연구진국외 연구진
분야 생명과학 > 생리학

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