2. Academic Validation
  3. Hepatic ENTPD5 Is Critical for Maintaining Metabolic Homeostasis and Promoting Brown Adipose Tissue Thermogenesis

Hepatic ENTPD5 Is Critical for Maintaining Metabolic Homeostasis and Promoting Brown Adipose Tissue Thermogenesis

  • Adv Sci (Weinh). 2025 Aug 11:e03603. doi: 10.1002/advs.202503603.
Rufeng Ma 1,  Song Hou 1,  Rui Xiang 1,  Wenjun Liu 1,  Xin Li 1,  Yujing Chi 2,  Ming Xu 3,  Haochen Yao 4,  Jing Li 5,  Jichun Yang 1 3
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China.
  • 2 Department of Central Laboratory and Institute of Clinical Molecular Biology, Department of Gastroenterology, Peking University People's Hospital, Beijing, 100044, China.
  • 3 Department of Cardiology, Peking University Third Hospital, Beijing, 100191, China.
  • 4 Hepatobiliary and Pancreatic Surgery Department, General Surgery Center, First Hospital of Jilin University, No.1 Xinmin Street, Changchun, Jilin, 130021, China.
  • 5 Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
PMID: 40788055 DOI: 10.1002/advs.202503603
Abstract

Although hepatocyte-released adenosine triphosphate (ATP) plays important roles in maintaining metabolic homeostasis, how its hydrolyzation outside hepatocytes impacts on glucolipid metabolism remains unclear. The authors aim to identify the enzyme(s) that hydrolyzes hepatocyte-secreted ATP to regulate metabolic homeostasis. All known ATP-hydrolyzing 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, P2Y12, 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-mediated 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.

Keywords

adenosine triphosphate metabolism; adrenomedullin; brown adipose tissue thermogenesis; ectonucleoside triphosphate diphosphohydrolase 5.

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