PPAR-gamma Ligands Can Induce HO-1 with/without Nrf2

Background: Dioxins and other environmental contaminants can lead to the bioaccumulation and the production of Tnf-a which can lead to activation of other cellular signal and inflammatory mediators. In addition, its expression can inhibit the expression of cellular proteins that are necessary for cellular functions and protection from inflammation. Some of these proteins can have both positive and negative effects. One such proteins is PPAR-gamma which is an important player in adipogenesis which if uncontrolled can lead to obesity. On the other hand, it has powerful cellular anti-inflammatory properties and regulates insulin sensitivity and fatty acid metabolism. Nrf2’s role in cells is to help modulate the expression of chemokines like Tnf-a. Its decrease may lead to overexpression of inflammatory proteins that alter cellular homeostasis. Nrf2 levels can fall due to aging, nutritional factors such as high-fat diets, interaction with other proteins etc. The AhR is one protein that interacts with Nrf2 to provide protective effects. The AhR also mediates toxicity from dioxin and other compounds similar to dioxins and can inhibit the activities of PPAR-gamma which may lead to weight loss and abnormal fatty acid metabolism. Other studies have shown this inhibition is not direct but acts through the activities of other proteins. Nrf2 also controls the levels of HO-1 which is an important anti-inflammatory, antioxidant and anti-apoptotic properties by acting through bilirubin/biliverdin and CO. Ho-1 has the ability to mediate adiponectin which can decrease fat content and inflammatory cytokines in diabetic rats. (Kim, Abraham) Cao’s findings show that HO-1 combined with increases in adiponectin in diabetes decreased oxidative stress and improved endothelial function and hypertension and also prevented apoptosis.

  

Fergusen demonstrates in fibroblasts that PPAR-gamma ligands can elevate the levels of HO-1 which as one author showed is independent, in this case, of Nrf2. In this study it was shown that two ligands of PPAR-gamma, CDDO and 15-PJG2 have potent anti-fibrotic effects in-vitro, also has the ability to upregulate HO-1 in lung fibroblasts. Ligands that do not have an electrophilic center did not elevate HO-1 in this study and the results show that these ligands induce HO-1 through a GSH-dependant mechanism. The author concludes from this study that electrophilic PPAR-gamma ligands have a clinical potential as anti-fibrotic agents by their activities on fibroblast function and indirectly activating antioxidant defenses. In this experiment, NAC prevented the upregulation of HO-1. Past studies have shown that PJG2 has the ability to enhance the expression of GSTA2 through Nrf2 and that PPAR-gamma can enhance this expression further. (Park)

Note:

• Oregano has the potential for preventing or reducing the effects of the metabolic syndrome which includes obesity, high blood sugar, high blood pressure and alteractions in lipid levels. Oregano binds but does not transactivate PPAR-gamma and contain a number of different chemicals that have been shown in studies to be of nutritional benefit. According to one author, "there may be a use for oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARα agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis. The results warrant further investigation of oregano extract for its potential to prevent and ameliorate metabolic syndrome and its complications."
• Quercetin (which is in oregano extract) can counteract ethanol-induced liver damage by upregulating HO-1. (Yao)
  

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