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

Sun，Hai Jian2,3; Tan，Jian Xin4; Shan，Xiao Dong5; Wang，Zi Chao3; Wu，Zhi Yuan2; Bian，Jin Song1,2; Nie，Xiao Wei2,4,6

2023-08-01

10.1016/j.metabol.2023.155579

Metabolism: Clinical and Experimental   影响因子和分区

0026-0495

1532-8600

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 (DVEDSYGQQWTYEQR) 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.

Autophagy Lipogenesis Na+/K+-ATPase SITR1 Steatosis

SCI

英语

其他

National Natural Science Foundation of China[81872865];National Natural Science Foundation of China[8217021262];National Medical Research Council[NMRC/1274/2010];National Medical Research Council[NMRC/CIRG/163/2013];

Endocrinology & Metabolism

Endocrinology & Metabolism

WOS:001054268400001

W B SAUNDERS CO-ELSEVIER INC

BIOLOGY & BIOCHEMISTRY

2-s2.0-85160233927

Scopus

1.Department of Pharmacology,School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China
2.Department of Pharmacology,Yong Loo Lin School of Medicine,National University of Singapore,Singapore
3.Department of Basic School,Wuxi School of Medicine,Jiangnan University,Wuxi,214122,China
4.Lung Transplant Group,Wuxi People's Hospital Affiliated to Nanjing Medical University,Wuxi,214023,China
5.Department of General Surgery,Affiliated Drum Tower Hospital,Medical School,Nanjing University,Nanjing,210008,China
6.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

Sun，Hai Jian,Tan，Jian Xin,Shan，Xiao Dong,et al. DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice[J]. Metabolism: Clinical and Experimental,2023,145.

Sun，Hai Jian.,Tan，Jian Xin.,Shan，Xiao Dong.,Wang，Zi Chao.,Wu，Zhi Yuan.,...&Nie，Xiao Wei.(2023).DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice.Metabolism: Clinical and Experimental,145.

Sun，Hai Jian,et al."DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice".Metabolism: Clinical and Experimental 145(2023).