Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome

Abstract

The global epidemic of obesity continues unabated with sequelae of diabetes and metabolic syndrome. This review reflects the dramatic increase in research on the role of increased expression of heme oxygenase (HO)-1/HO-2, biliverdin reductase, and HO activity on vascular disease. The HO system engages with other systems to mitigate the deleterious effects of oxidative stress in obesity and cardiovascular disease (CVD). Recent reports indicate that HO-1/HO-2 protein expression and HO activity have several important roles in hemostasis and reactive oxygen species (ROS)-dependent perturbations associated with metabolic syndrome. HO-1 protects tissue during inflammatory stress in obesity through the degradation of pro-oxidant heme and the production of carbon monoxide (CO) and bilirubin, both of which have anti-inflammatory and anti-apoptotic properties. By contrast, repression of HO-1 is associated with increases of cellular heme and inflammatory conditions including hypertension, stroke, and atherosclerosis. HO-1 is a major focus in the development of potential therapeutic strategies to reverse the clinical complications of obesity and metabolic syndrome.

Figure 1

Obesity increases risk for cardiovascular disease. Obesity leads to an increase in ROS within adipocytes, accomplished by increasing NADPH oxidase activity, mitochondrial ROS production, and heme levels while repressing antioxidative enzymes such as HO-1 and SOD. This increase in adipocyte ROS and heme leads to increased adipocyte differentiation, maturation, resulting in increased production of proinflammatory compounds such as cytokines and decreased production of antioxidative compounds and compounds preventing adipocyte growth and differentiation. The consequences of obesity-mediated adipocyte dysfunction may lead to vascular dysfunction which is a prelude to vascular disease and hypertension.

Figure 2

Drug actions in the heme degradation pathway. HO-1 (inducible) and HO-2 (constitutive) cleave free heme or denatured heme proteins to generate CO, ferritin, and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase. CO has both anti-inflammatory and anti-apoptotic properties ^,,,, Ferritin is essential for cellular redox reactions ^,, Serum bilirubin levels are positively linked with a decreased risk of CVD and protection against diabetes and vascular dysfunction ^,. Drugs focused on the heme degradation pathway predominantly induce HO-1 activity, possibly by interacting with the gene promoter. Biliverdin reductase functions via a direct increase of HO-1 or an increase in bilirubin levels to promote a reduction in oxidative species ^,. And mesobiliverdin enhances β-cell function in the pancreas through its antioxidant properties This pathway provides the basis for multiple pharmaceutical and genetic agents that can protect against CVD by increasing HO-1 expression.

Figure 3

Heme synthethic pathway. The rate-limiting synthetic enzymes are believed to be ALA synthase and, in part, porphobilinogen deaminase (PBGD). Both enzymes exist in adipocytes and in erythroid and non-erythroid forms. In non-erythroid cells such as liver, kidney, heart, ALA synthase essentially plays a housekeeping role, maintaining intracellular heme levels. High levels of heme thus repress the synthesis of ALA synthase while stimulating heme degradation through the induction of HO-1 ^,. In the origin of hematopoietic-derived cells such as adipocyte and erythroid cells, heme is essential for cellular proliferation and differentiation ^,,, and increase ALA synthase mRNA levels and enzyme activity. Further, excess heme enhances the synthesis of globin mRNA An iron-binding element has been located on the 5’ untranslated region of the erythroid type cells ALA synthase, so it is possible that the enzyme is actually regulated by intracellular levels of iron. Thus, an increase in heme may induce HO, increasing the levels of free iron which in turn stimulate the formation of adipocyte ALA synthase mRNA and adipocyte during differentiations.

Figure 4

Schematic representation of the potential mechanism of HO-1 signaling pathways. HO-1 signaling pathways act to improve vascular function and attenuate adiposity adipocyte differentiation. Some of these signaling targets are insulin receptors, adiponectin, via an increase in small adipocytes, EET, SIRT-1, Wnt10b, and β-catenin. The decrease in ROS as a result of an increase of HO-1 and HO-1 derived biliverdin/bilirubin provides stability to EET, leading to an enhancement of insulin sensitivity and an increase in vascular function. HO-1 also translocates into the mitochondria, increasing mitochondrial biogenesis and transport carriers and decreasing mitochondrial ROS ^,,.

Figure 5

Pleiotropic effect of HO-1 on obesity and CVD. HO-1 has a diverse range of actions on blood vessel endothelial tissue, decreasing inflammation ^,,,– and vasoconstriction ^, while increasing vasodilation ^,,, endothelial progenitor cells and endothelial and cardiac cell function ^,,,,,–. As seen on the scheme, HO-1, bilirubin, and CO decrease pro-inflammatory molecules ^,,–, angiotensin II ^,,–, free radicals ^,, VSM proliferation ^,,–, LDL ^,, endothelin ^–, and IL-18 . The overall effect is the amelioration of cardiovascular disease and protection against the development of a disease state.