Introduction: Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes. Methods: To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining. Results: During adipogenesis in vitro, differentiating pre-adipocytes display transient increases in the expression of genes involved in canonical Wnt signaling cascade. Increased levels of HO-1 expression and HO activity resulted in elevated levels of β-catenin, pGSK3β, Wnt10b, Pref-1, and shh along with increased levels of adiponectin (P < 0.05). In addition, induction of HO-1 resulted in a reduction in C/EBPα, PPARγ, Peg-1/Mest, aP2, CD36 expression and lipid accumulation (P < 0.05). Suppression of HO-1 gene by siRNA decreased Wnt10b, pGSK3β and β-catenin expression, and increased lipid accumulation. The canonical Wnt responsive genes, IL-8 and SFRP1, were upregulated by CoPP and their expression was decreased by the concurrent administration of tin mesoporphyrin (SnMP), an inhibitor of HO activity. Furthermore, knockdown of Wnt10b gene expression by using siRNA showed increased lipid accumulation, and this effect was not decreased by concurrent treatment with CoPP. Also our results show that blocking the Wnt 10b antagonist, Dickkopf 1 (Dkk-1), by siRNA decreased lipid accumulation and this effect was further enhanced by concurrent administration of CoPP. Conclusions: This is the first study to demonstrate that HO-1 acts upstream of canonical Wnt signaling cascade and decreases lipogenesis and adipocyte differentiation suggesting that the HO-1 mediated increase in Wnt10b can modulate the adipocyte phenotype by regulating the transcriptional factors that play a role in adipogenesis. This is evidenced by a decrease in lipid accumulation and inflammatory cytokine levels, increased adiponectin levels and elevation of the expression of genes of the canonical Wnt signaling cascade.

Na/K-ATPase has been extensively studied for its ion pumping function, but, in the past several decades, has been identified as a scaffolding and signaling protein. Initially it was found that cardiotonic steroids (CTS) mediate signal transduction through the Na/K-ATPase and result in the generation of reactive oxygen species (ROS), which are also capable of initiating the signal cascade. However, in recent years, this Na/K-ATPase/ROS amplification loop has demonstrated significance in oxidative stress related disease states, including obesity, atherosclerosis, heart failure, uremic cardiomyopathy, and hypertension. The discovery of this novel oxidative stress signaling pathway, holds significant therapeutic potential for the aforementioned conditions and others that are rooted in ROS.

Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.

The Na/K-ATPase amplifies oxidant signaling, and its attenuation with pNaKtide antagonizes adipogenesis.

We have previously reported that the sodium potassium adenosine triphosphatase (Na/K-ATPase) can effect the amplification of reactive oxygen species. In this study, we examined whether attenuation of oxidant stress by antagonism of Na/K-ATPase oxidant amplification might ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy (PNx). PNx induced the development of cardiac morphological and biochemical changes consistent with human uremic cardiomyopathy. Both inhibition of Na/K-ATPase oxidant amplification with pNaKtide and induction of heme oxygenase-1 (HO-1) with cobalt protoporphyrin (CoPP) markedly attenuated the development of phenotypical features of uremic cardiomyopathy. In a reversal study, administration of pNaKtide after the induction of uremic cardiomyopathy reversed many of the phenotypical features. Attenuation of Na/K-ATPase oxidant amplification may be a potential strategy for clinical therapy of this disorder.