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  3. PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis

PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis

  • Mil Med Res. 2024 Jun 27;11(1):41. doi: 10.1186/s40779-024-00543-6.
Cheng-Qing Hu # 1 2,  Tao Hou # 1,  Rui Xiang 1,  Xin Li 1,  Jing Li 3,  Tian-Tian Wang 1,  Wen-Jun Liu 1,  Song Hou 1,  Di Wang 4,  Qing-He Zhao 5,  Xiao-Xing Yu 1,  Ming Xu 6,  Xing-Kai Liu 7,  Yu-Jing Chi 8 9,  Ji-Chun Yang 10 11
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 Obstetrics and Gynecology, Peking University Third Hospital/National Clinical Research Center for Obstetrics and Gynecology, Beijing, 100191, China.
  • 3 Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
  • 4 Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing, 100044, China.
  • 5 Department of Gastroenterology, Peking University People's Hospital, Beijing, 100044, China.
  • 6 Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital/Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Beijing, 100191, China.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, General Surgery Centre, the First Hospital of Jilin University, Changchun, 130061, China. xingkailiu@foxmail.com.
  • 8 Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing, 100044, China. chiyujing@bjmu.edu.cn.
  • 9 Department of Gastroenterology, Peking University People's Hospital, Beijing, 100044, China. chiyujing@bjmu.edu.cn.
  • 10 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. yangj@bjmu.edu.cn.
  • 11 Department of Cardiology, Peking University Third Hospital, Beijing, 100191, China. yangj@bjmu.edu.cn.
  • # Contributed equally.
PMID: 38937853 DOI: 10.1186/s40779-024-00543-6
Abstract

Background: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet β cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed.

Methods: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), Insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays.

Results: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated Calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers.

Conclusions: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.

Keywords

Adenosine triphosphate (ATP) release; Family with sequence similarity 3 member A (FAM3A); Glucolipid metabolism; Pannexin 1 (PANX1).

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