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The authors aim to identify the enzyme(s) that hydrolyzes hepatocyte\u2010secreted ATP to regulate metabolic homeostasis. All known ATP\u2010hydrolyzing enzymes are expressed with the highest expression of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) in hepatocytes. ENTPD5 expression is reduced in steatotic mouse and human livers. Hepatic ENTPD5 overexpression ameliorates the deregulated glucolipid metabolism and obesity with increased brown adipose tissue (BAT) thermogenesis, while hepatic ENTPD5 silencing exerted the opposite effects in obese mice. Mechanistically, ENTPD5 hydrolyzes extracellular ATP to ADP, which activates purinergic receptor, P2Y\n                    <jats:sub>12<\/jats:sub>\n                    , to inhibit gluconeogenesis and lipid deposition, and repress adrenomedullin (ADM) expression. Hepatic ENTPD5 repression promotes ADM expression and release to inhibit uncoupling protein 1 (UCP1) expression and thermogenesis in BAT. Hepatic ADM expression is increased in NAFLD patients. Serum ADM level is correlated positively with Body mass index in overweighted or obese humans. Hepatic ADM silencing promotes UCP1 expression and thermogenesis in BAT of obese mice. Overall, ENTPD5\u2010mediated hydrolysis of extracellular ATP to ADP of hepatocytes is critical for maintaining hepatic glucose\/lipid metabolism and promoting BAT thermogenesis by inhibiting ADM expression and secretion.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503603","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T13:06:24Z","timestamp":1754917584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hepatic ENTPD5 Is Critical for Maintaining Metabolic Homeostasis and Promoting Brown Adipose Tissue Thermogenesis"],"prefix":"10.1002","volume":"12","author":[{"given":"Rufeng","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Center for Non\u2010coding RNA Medicine Peking University Health Science Center  Beijing 100191 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