2. Academic Validation
  3. Cross-organ metabolite production and consumption in healthy and atherogenic conditions

Cross-organ metabolite production and consumption in healthy and atherogenic conditions

  • Cell. 2025 May 20:S0092-8674(25)00512-4. doi: 10.1016/j.cell.2025.05.001.
Hosung Bae 1,  Sunhee Jung 1,  Johnny Le 1,  Ian Tamburini 1,  Joohwan Kim 2,  Eric Wang 3,  Won-Suk Song 1,  Wonsuk Choi 1,  Ki-Hong Jang 2,  Taekyung Kang 1,  Miranda L Lopez 4,  Cuauhtemoc Ramirez 5,  Ipsita Mohanty 6,  Miranda E Kelly 1,  Jessie Kim 1,  Raymond Kim 1,  Sang Hee Park 1,  Jongwon Baek 1,  Bryan Mendez 1,  Paul Petrus 7,  Thomas Q de Aguiar Vallim 8,  Dequina A Nicholas 9,  Quinton Smith 10,  Gina Lee 11,  Marcus Seldin 12,  Cholsoon Jang 13
Affiliations

Affiliations

  • 1 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
  • 2 Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA.
  • 3 Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA.
  • 4 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
  • 5 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA.
  • 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
  • 7 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden.
  • 8 Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 9 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA.
  • 10 Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA; Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • 11 Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA.
  • 12 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA. Electronic address: mseldin@uci.edu.
  • 13 Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA. Electronic address: choljang@uci.edu.
PMID: 40436017 DOI: 10.1016/j.cell.2025.05.001
Abstract

Mammalian organs continuously produce and consume circulating metabolites for organismal health and survival. However, the landscape of this fundamental process and its perturbation by diet and disease is unknown. Using arteriovenous metabolomics, tissue transcriptomics, and hormone arrays in multiple pathophysiological conditions in pigs, we generated an atlas of 10 cross-organ metabolite production and consumption during fasting/feeding, Western diet, and Cardiovascular Disease progression induced by low-density lipoprotein receptor (LDLR) deficiency. We discovered numerous instances of feeding-dependent and -independent metabolite production and consumption by organs and proposed mechanisms by which these are disrupted by Western diet via altered metabolite concentration gradients and Hormones. Both Western diet and LDLR deficiency trigger the release of bile acids (BAs) by extra-hepatic organs, likely contributing to abnormally elevated circulating BA levels and consequent vascular inflammation and atherosclerosis development. These resources reveal intricate inter-organ metabolic crosstalk across pathophysiological conditions, offering biochemical insights into diet effects and cardiometabolic diseases.

Keywords

arteriovenous metabolomics; bile acid metabolism; cardiovascular disease; circulating metabolite; flux; inter-organ exchange; isotope tracing; low-density lipoprotein receptor; metabolomics; western diet.

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