2. Academic Validation
  3. DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice

DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice

  • Metabolism. 2023 Apr 29;155579. doi: 10.1016/j.metabol.2023.155579.
Hai-Jian Sun 1,  Jian-Xin Tan 2,  Xiao-Dong Shan 3,  Zi-Chao Wang 4,  Zhi-Yuan Wu 5,  Jin-Song Bian 6,  Xiao-Wei Nie 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Basic School, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
  • 2 Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China.
  • 3 Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China.
  • 4 Department of Basic School, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
  • 5 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 6 Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: bianjs@sustech.edu.cn.
  • 7 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China; Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen 518020, China. Electronic address: niexw2021@mail.sustech.edu.cn.
PMID: 37127227 DOI: 10.1016/j.metabol.2023.155579
Abstract

Background: Na+/K+-ATPase (NKA), an ion pumping Enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However, the role of NKA in hepatic lipid homeostasis has yet to be fully characterized.

Methods: The activity of NKA and NKAα1 expression were determined in steatotic cells, mice and patients. The roles of NKAα1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKAα1 in mice.

Results: Herein, we demonstrated that the expression and activity of α1 subunit of NKA (NKAα1) were lowered in the livers of nonalcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-induced obese mice, and genetically obese (ob/ob, db/db) mice, as well as oleic acid-induced hepatocytes. Hepatic deficiency of NKAα1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKAα1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKAα1 upregulated Sirtuin 1 (SIRT1) via interacting with ubiquitin specific peptidase 22 (USP22), a deubiquitinating Enzyme for the stabilization and deubiquitination of SIRT1, thus activating the downstream Autophagy signaling. Blockade of the SIRT1/Autophagy signaling pathway eliminated the protective effects of NKAα1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (897DVEDSYGQQWTYEQR911) of NKAα1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKAα1 and inducing its activation.

Conclusions: Collectively, this study renews the functions of NKAα1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKAα1.

Keywords

Autophagy; Lipogenesis; Na(+)/K(+)-ATPase; SITR1; Steatosis.

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