第1480回生物科学セミナー
Disrupted circulating metabolite exchange across organs by the Western diet
Cholsoon Jang, PhD（Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.）
2023年12月13日(水) 9:00-10:30 Zoomによるweb講義
Mammalian organs convert dietary nutrients into circulating metabolites and share them to maintain whole body metabolic homeostasis. The most famous example is the Cori cycle between liver and muscle for glucose-lactate exchange. However, our understanding of this fundamental process is limited to only a few metabolites, organs and conditions. To comprehensively explore this process and obtain novel insights into disease connections, here we employed arteriovenous (AV) metabolomics using unconventional animal model (pigs) and high-resolution liquid chromatography-mass spectrometry. We systematically elucidated the pre- and post-prandial metabolic exchanges across 10 organs in pigs fed either a normal or a high-fat/high-sucrose diet (HFHS). Our analysis detected a total of 1304 (normal) and 1369 (HFHS) statistically significant metabolite exchange events across organs. In pigs-fed a normal diet, metabolite exchanges are evenly distributed across organs during fasting whereas postprandial metabolism (at 30 and 60 min after feeding) primarily occurs in the gastrointestinal organs but also happen in other peripheral organs. Such inter-organ dynamics return to fasting-like conditions at 120 min after feeding, reflecting metabolic homeostasis achieved. In contrast, feeding the HFHS diet just for 2 weeks severely attenuated postprandial inter-organ metabolic exchanges. Metabolic pathway analysis revealed that the most significantly changed circulating metabolites are cholesterols, ceramides, and bile acids, all of which are well-known cardiovascular disease risk factors. These metabolites are aberrantly produced and released by multiple organs only in pigs fed the HFHS diet. Cross-organ RNA sequencing further revealed ectopically expressed synthesis enzymes and induction of known transcriptional regulators. Altogether, our study reveals previously unrecognized multi-organ landscape of postprandial metabolite trafficking under both normal and diabetogenic dietary conditions and provides potential mechanisms of how HFHS diet enhances cardiovascular disease risks via disrupted cross-organ metabolic homeostasis.
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担当： 理学系研究科 生物科学専攻 生物情報科学科 黒田研究室 黒田 真也
