Molecular and Cellular Biochemistry

, Volume 440, Issue 1–2, pp 77–88 | Cite as

Regulation of hepatic Na+/K+-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK

  • Julijana Stanimirovic
  • Milan Obradovic
  • Anastasija Panic
  • Voin Petrovic
  • Dragan Alavantic
  • Irena Melih
  • Esma R. Isenovic


In this study, we assessed whether the disturbed regulation of sodium/potassium-adenosine-triphosphatase (Na+/K+-ATPase) occurs as a consequence of obesity-induced IR in sex-specific manner. We also assessed whether alterations of IRS/PI3K/Akt, ERK1/2, AMPKα, and RhoA/ROCK signaling cascades have an important role in this pathology. Female and male Wistar rats (150–200 g, 8 weeks old) were fed a standard laboratory diet or a high-fat (HF) diet (42% fat) for 10 weeks. The activity of hepatic Na+/K+-ATPase and Rho, and the association of IRS-1/p85 were assessed in liver. Furthermore, the protein level of α1 Na+/K+-ATPase in plasma membrane fractions, and protein levels of IRS-1, PI3K-p85, -p110, RhoA, ROCK1, ROCK2, ERK1/2, AMPKα, ERα, and ERβ in liver lysates were assessed. The expression of hepatic α1 Na+/K+-ATPase mRNA was also analyzed by qRT-PCR. The results show that HF-fed female rats exhibited an increase in hepatic ERK1/2 (p < 0.05) and AMPKα (p < 0.05) phosphorylation levels, unchanged level of Na+/K+-ATPase α1 mRNA, decreased level of Na+/K+-ATPase activity (p < 0.05), and decreased α1 Na+/K+-ATPase protein expression (p < 0.01). In liver of HF-fed male rats, results show decreased levels of Na+/K+-ATPase activity (p < 0.01), both protein and mRNA of α1 subunit (p < 0.05), but significant increase in Rho activity (p < 0.05). Our results indicate significant sex differences in α1 Na+/K+-ATPase mRNA expression and activation of ERK1/2, AMPKα, and Rho in the liver. Exploring the sex-specific factors and pathways that promote obesity-related diseases may lead to a better understanding of pathogenesis and discovering new therapeutic targets.


High-fat diet Insulin resistance Liver Na+/K+-ATPase Sex differences 



Protein kinase B


AMP-activated protein kinase


Estrogen receptor


Extracellular signal-regulated kinases 1 and 2




Insulin resistance


Insulin receptor substrate




Phosphatidyl inositol 3 kinase


GTP-binding protein family


GTP-binding protein


Rho-associated protein kinase











This work is supported by the Grants No. 173033 (to E.R.I.) and III41028 (to D.A.) from the Ministry of Science, Republic of Serbia.

Compliance with ethical standards

Conflict of interest

The authors declare that they do not have conflict of interest.


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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Laboratory of Radiobiology and Molecular GeneticsVinca Institute of Nuclear Sciences, University of BelgradeBelgradeSerbia
  2. 2.Laboratory of Physical ChemistryVinca Institute of Nuclear Sciences, University of BelgradeBelgradeSerbia
  3. 3.Department of Cancer Research and Molecular Medicine, Faculty of MedicineNorwegian University of Science and Technology (NTNU)TrondheimNorway
  4. 4.Faculty of Dentistry in PancevoUniversity Business AcademyBelgradeSerbia

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