DR region of NKAa1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice

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 NKA & alpha;1 expression were determined in steatotic cells, mice and patients. The roles of NKA & alpha;1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKA & alpha;1 in mice.Results: Herein, we demonstrated that the expression and activity of & alpha;1 subunit of NKA (NKA & alpha;1) 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 NKA & alpha;1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKA & alpha;1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKA & alpha;1 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 NKA & alpha;1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (897DVEDSYGQQWTYEQR911) of NKA & alpha;1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKA & alpha;1 and inducing its activation.Conclusions: Collectively, this study renews the functions of NKA & alpha;1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKA & alpha;1.