DR region of NKAα1 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 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.

Are Chinese Patients with Type 2 Diabetes and a Body Mass Index of 27.5-32.5 kg/m2 Suitable for Metabolic Surgery? A One-Year Post-Surgery Study.

INTRODUCTION: The aim of this study was to clarify the efficacy and safety of metabolic surgery in Chinese patients with type 2 diabetes mellitus (T2DM) and a body mass index (BMI) of 27.5-32.5 kg/m2. METHODS: A total of 99 patients with T2DM were enrolled in this retrospective cohort study. Of these patients, 53 had a BMI of 27.5-32.5 kg/m2 and had undergone metabolic surgery (n = 21) or were on conventional antidiabetic therapy (n = 32)]; 46 had a BMI ≥ 32.5 kg/m2 and all had undergone metabolic surgery. Primary endpoints included the triple endpoint [hemoglobin A1c < 6.5%, low-density lipoprotein cholesterol (LDL-C) < 2.6 mmol/L, and systolic blood pressure (SBP) < 130 mmHg] and successful weight loss 1 year later. Remission of diabetes, glucose and lipid metabolism, medication usage, and adverse events were evaluated. RESULTS: Of patients with BMI 27.5-32.5 kg/m2 undergoing metabolic surgery, 33.33% achieved the composite endpoints, and 100% achieved successful weight loss. This result was similar to that in patients with BMI ≥ 32.5 and better than those with BMI 27.5-32.5 kg/m2 receiving conventional antidiabetic therapy. A significant and similar reduction in BMI, waist circumference, SBP, serum LDL-C, hemoglobin A1c, and uric acid, as well as similar frequency postoperative adverse events, were confirmed in both metabolic surgery groups. Patients with BMI 27.5-32.5 kg/m2 who had undergonemetabolic surgery showed more metabolic improvement than those only receiving medications but they experienced more adverse events. CONCLUSION: A BMI cutoff of 27.5 kg/m2 for metabolic surgery may be suitable for Chinese patients with T2DM.

Olfactory epithelium neural stem cell implantation restores noise-induced hearing loss in rats.

OBJECTIVE: In this study, we aimed to elucidate the restorative effects of olfactory epithelium neural stem cells (oe-NSCs) implantation on noise-induced hearing loss and establish their mechanism of action. METHODS: To model hearing loss, rats were subjected to consecutive seven-day noise exposure. Then, oe-NSCs were implanted into cochlear tissue by retroauricular approach. Auditory brainstem response (ABR) method was used to evaluate the hearing function. Immunohistochemical staining was utilized to determine cell survival and migration of oe-NSCs. After IL-1ß stimulation, nerve growth factor (NGF), neurotrophin-3 (NT-3), and NT-4 levels were evaluated in oe-NSCs. The protective action of oe-NSCs against hydrogen peroxide-induced cell injury was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). RESULTS: oe-NSCs implantation into cochlear tissues ameliorated the noise-induced hearing impairment (p<0.05). After implantation, green fluorescent cells were observed in an even suspension in the lymph fluid of the cochlea, and 65% of the GFP(+) cells reached the cochlear duct wall three days after implantation, but did not expand to the Corti-organ. After IL-1ß stimulation, olfactory epithelial stem cell increased their secretion of NGF and NT-3 (p<0.05), but not that of NT-4. TUNEL assay results revealed that oe-NSCs co-culturing with injured neurons reduced the apoptotic cell death induced by hydrogen peroxide. CONCLUSION: After transplantation into the inner ear, oe-NSCs not only survived, but also migrated around the spiral ganglion neurons (SGNs) in Rosenthal's canal (RC). Hearing loss induced by noise exposure was restored after oe-NSCs implantation. Mechanically, oe-NSCs secreted NGF and NT-3, which likely contributed to the prevention of neuronal injury. This study provides novel data in support of the effective action of implanted oe-NSCs in the restoration of noise-induced hearing loss in a rat model.