RETRACTED ARTICLE: pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet

Abstract

We have previously reported that the α1 subunit of sodium potassium adenosine triphosphatase (Na/K-ATPase), acts as a receptor and an amplifier for reactive oxygen species, in addition to its distinct pumping function. On this background, we speculated that blockade of Na/K-ATPase-induced ROS amplification with a specific peptide, pNaKtide, might attenuate the development of steatohepatitis. To test this hypothesis, pNaKtide was administered to a murine model of NASH: the C57Bl6 mouse fed a “western” diet containing high amounts of fat and fructose. The administration of pNaKtide reduced obesity as well as hepatic steatosis, inflammation and fibrosis. Of interest, we also noted marked improvement in mitochondrial fatty acid oxidation, insulin sensitivity, dyslipidemia and aortic streaking in this mouse model. To further elucidate the effects of pNaKtide on atherosclerosis, similar studies were performed in ApoE knockout mice also exposed to the western diet. In these mice, pNaKtide not only improved steatohepatitis, dyslipidemia, and insulin sensitivity, but also ameliorated significant aortic atherosclerosis. Collectively, this study demonstrates that the Na/K-ATPase/ROS amplification loop contributes significantly to the development and progression of steatohepatitis and atherosclerosis. And furthermore, this study presents a potential treatment, the pNaKtide, for the metabolic syndrome phenotype.

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

“…Chronic obesity and an increase of visceral fat is associated with adipocyte dysfunction that contributes to an increase in reactive oxygen species (ROS) and changes in adipocyte-derived paracrine factors [1], [2], [3]. Obesity-mediated development of hyperglycemia suppresses HO-1 levels [4], [5], [6].…”

Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis

“…Recently published studies demonstrated the role of Na/K-ATPase signaling in aggravating oxidative stress and subsequent NASH using in vivo models of a WD diet. These studies extensively illustrated increased hepatic triglycerides levels, hepatic ALT, FFA, FAS and CD36 expression in mice fed a WD diet [9]. This lipid accumulation was confirmed by the histological findings of liver tissues, which exhibited a large number of vacuoles in the liver, significant inflammation and inflammatory cell infiltration into the liver.…”

“…The Na/K-ATPase signaling cascade has been extensively studied due to its recently elucidated role as a scaffolding and signaling protein. Studies over the last two decades, since the emergence of the Xie Model of Na/K-ATPase signaling, have demonstrated that activation of this signaling pathway is pivotal in exacerbating oxidative stress in several disease models [8,9,17,18]. While several subunits of Na/K-ATPase have been dissected and known to be involved in its distinct ion pumping function, the α1 subunit of Na/K-ATPase signaling primarily causes its structural modulation leading to the activation of membrane-bound tyrosine kinase protein, Src [19,20].…”

“…Oxidative stress-induced adipogenesis and adipocyte phenotypic alterations increase adipogenic markers such as peroxisome proliferation factor-γ (PPAR-γ), fatty acid synthase (FAS) and mesoderm-specific transcript protein (Mest) along with pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) [8]. The excessive production of ROS and subsequent oxidative stress, in obesity, can also be partly attributed to the mitochondrial dysfunction and the altered state of mitochondrial biogenesis [9]. To this end, several studies have also demonstrated the important role of interferon-gamma (IFN-γ) in diet-induced obesity, which regulates systemic inflammation and insulin resistance in obesity [46,47].…”

“…The trigger of these signaling pathways activates mediators associated with the overproduction of ROS and inflammatory markers, hence creating a ROS amplification loop, exacerbating the already existing condition. The cumulative line of evidence suggests that the trigger of downstream signaling pathways mediated through activation of Na/K-ATPase signaling alters the adipocyte phenotype, induces mitochondrial dysfunction, modulates transcriptional and post-transcriptional regulation and, consequently, altering the systemic metabolic profile [8,9]. Hence, understanding the intersection of Na/K-ATPase oxidant amplification and redox imbalance in the obesity-associated phenotype can provide a viable target for disease intervention.…”