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A liberação de ATP mediada por PANX1 confere os efeitos supressores de FAM3A na gluconeogênese e lipogênese hepáticas

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    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

    Department of Obstetrics and Gynecology, Peking University Third Hospital/National Clinical Research Center for Obstetrics and Gynecology, Beijing 100191, China

Cheng-Qing Hu12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    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

Tao Hou1,  
  • Affiliation：

    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

Rui Xiang1,  
  • Affiliation：

    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

Xin Li1,  
  • Affiliation：

    Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China

Jing Li3,  
  • Affiliation：

    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

Tian-Tian Wang1,  
  • Affiliation：

    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

Wen-Jun Liu1,  
  • Affiliation：

    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

Song Hou1,  
  • Affiliation：

    Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China

Di Wang4,  
  • Affiliation：

    Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China

Qing-He Zhao5,  
  • Affiliation：

    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

Xiao-Xing Yu1,  
  • Affiliation：

    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

Ming Xu6,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Hepatobiliary and Pancreatic Surgery, General Surgery Centre, the First Hospital of Jilin University, Changchun 130061, China

  • Email：xingkailiu@foxmail.com
  • Introduction：* xingkailiu@foxmail.com
Xing-Kai Liu7*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China

    Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China

  • Email：chiyujing@bjmu.edu.cn
  • Introduction：chiyujing@bjmu.edu.cn
Yu-Jing Chi45*,  
  • role： Corresponding author通信作者
  • Affiliation：

    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

    Department of Cardiology, Peking University Third Hospital, Beijing 100191, China

  • Email：yangj@bjmu.edu.cn
  • Introduction：yangj@bjmu.edu.cn
Ji-Chun Yang18*

Resumo

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.

Palavras-chave

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

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