Animal and human tissue Na,K‐ATPase in normal and insulin‐resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects

Abstract

The sodium(Na)- and potassium(K)-activated adenosine-triphosphatase (Na,K-ATPase) is a membrane enzyme that energizes the Na-pump by hydrolysing adenosine triphosphate and wasting energy as heat, so playing a role in thermogenesis and energy balance. Na,K-ATPase regulation by insulin is controversial; in tissue of hyperglycemic-hyperinsulinemic ob/ob mice, we reported a reduction, whereas in streptozotocin-treated hypoinsulinemic-diabetic Swiss and ob/ob mice we found an increased activity, which is against a genetic defect and suggests a regulation by hyperinsulinemia. In human adipose tissue from obese patients, Na,K-ATPase activity was reduced and negatively correlated with body mass index, oral glucose tolerance test-insulinemic area and blood pressure. We hypothesized that obesity is associated with tissue Na,K-ATPase reduction, apparently linked to hyperinsulinemia, which may repress or inactivate the enzyme, thus opposing thyroid hormones and influencing thermogenesis and obesity development. Insulin action on Na,K-ATPase, in vivo, might be mediated by the high level of non-esterified fatty acids, which are circulating enzyme inhibitors and increase in obesity, diabetes and hypertension. In this paper, we analyse animal and human tissue Na,K-ATPase, its level, and its regulation and behaviour in some hyperinsulinemic and insulin-resistant states; moreover, we discuss the link of the enzyme with non-esterified fatty acids and attempt to interpret and organize in a coherent view the whole body of the exhaustive literature on this complicated topic.

Effects of obesity and estradiol on Na+/K+-ATPase and their relevance to cardiovascular diseases

“…Furthermore, Lin et al (1978Lin et al ( , 1981 have shown that the protein levels of Na C /K C -ATPase subunits are lower in the skeletal muscle and liver of adult obese (ob/ob) mice than in those of their lean counterparts, probably due to the decrease in the number of enzyme units. This, of course, cannot be due to an inhibitory effect, but could be the result of a repressing effect (Iannello et al 2007a). In this context, Guernsey & Morishige (1979) have also shown the reduction of Na C /K C -ATPase activity in ob/ob mice (Fig.…”

Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia

“…Clinical data indicate that impairment of glucose tolerance and DM both represent potential risk factors of PE [4,5]. In diabetics, perturbed NKA function is linked to impaired tissue insulin resistance, renal sodium retention, and development of hypertension, generation of reactive oxygen species, and cardiovascular remodeling [3,6,7]. Recently, we demonstrated that in experimental rats and patients with type 1 and type 2 DM, inhibiton of NKA is accompanied by elevated levels of marinobufagnin (MBG), an endogenous bufadienolide CTS, a vasoconstrictor and a natriuretic [8,9].…”

Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet

“…In cardiac muscle, Na + /K + -ATPase plays a crucial role in the regulation of cardiac electrophysiology and cardiomyocytes contractility, while various cardiac disorders including cardiac hypertrophy and hypertension, which commonly occur as a consequence of obesity, are associated with reduction of Na + /K + -ATPase activity and expression [18,19,41,37]. We have previously reported that in the hypertrophic heart of male rats a HF diet reduces the activity and expression of the ɑ1 and ɑ2 subunits of Na + /K + -ATPase, while estradiol treatment reduced heart hypertrophy and increased Na + /K + -ATPase expression/activity [42,39].…”

“…Furthermore, obesity is associated with the reduction of Na + /K + -ATPase activity in heart, skeletal muscle and liver, probably due to the development of IR since it has been shown that INS induces translocation of Na + /K + -ATPase subunits from intracellular stores to plasma membrane by a phosphatidylinositol 3-kinase (PI3K) dependent pathway [16][17][18][19]. In addition, gender-specific regulation of Na + /K + -ATPase exist, and estradiol exerts its cardioprotective effects partially by up-regulating Na + /K + -ATPase activity/expression [20][21][22].…”