Feature Review
Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome

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Obesity is a major risk factor in the development of diabetes, hypertension, fatty liver, and CVD.

HO-1 and HO-2 catalyze the breakdown of heme, a potentially harmful pro-oxidant, into potent anti-oxidants such as biliverdin/bilirubin and CO, with an anti-inflammatory effect.

This is the first review to discuss translational research that summarizes human genetic polymorphism of HO-1 and the effectiveness of bilirubin to ameliorate CVD.

This review uncovers a mechanistic link between obesity and the vascular system, and provides a conceptual basis for developing new drugs for the management of metabolic syndrome.

We provide a conceptual basis for the development of new therapeutic strategies that target HO-1 and biliverdin to ameliorate obesity, adipocyte (fat stem cell) dysfunction, and vascular dysfunction associated with the metabolic syndrome.

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.

Section snippets

Obesity and Metabolic Syndrome

Obesity and metabolic syndrome have earned the name ‘the silent disease’ because their adverse effects are insidious. Although obesity and metabolic syndrome are theoretically treatable with modern medical and lifestyle management, this is not a trivial undertaking. While a discussion about the long-term success of different therapeutic strategies addressing obesity and metabolic syndrome is beyond the scope of this introduction, it is fair to say that our national and regional battle with this

Heme Oxygenase

HO exists in two forms, HO-1, the inducible form, and HO-2, the constitutive form. Both isozymes degrade heme in an identical stereospecific manner to biliverdin with the concurrent release of CO and iron [25]. In mammals, biliverdin is rapidly reduced by biliverdin reductase to bilirubin 26, 27. HO-1 and HO-2 are alike in terms of mechanism, cofactor and substrate requirements, and their susceptibility to inhibition by synthetic metalloporphyrins in which the central iron atom is replaced by

Biological Action of Bilirubin/Biliverdin

The biologic actions of HO-1-derived bilirubin may be especially relevant to the prevention of oxidant-mediated cell death 10, 11, 60 (Figure 2). Bilirubin, at a low concentration, scavenges ROS, thereby reducing oxidant-mediated cellular damage and attenuating oxidant stress in vivo [52]. The roles of biliverdin and bilirubin in counteracting oxidative and nitrosative stress have been extensively reviewed [32]. Administration of the degradation products of heme confers protection against

Biological Action of CO

The function of CO is unclear. It is generally accepted that CO is toxic to cells, but less is known about pico-levels of CO in physiological function (reviewed in [74]). A dose-dependent toxic effect of CO on BSC-1 cells established that this was due to stimulation of iNOS and production of nitrate NOO, which is known to cause cellular injury 75, 76. Although CO, similarly to NO, functions as a vasorelaxant via stimulation of sGC, the relative potency of CO is miniscule compared to that of

Biological Action of Ferritin

Heme metabolism results in the liberation of iron, and tissues rely on storage proteins to regulate ‘free’ levels of this metal. Free iron is well known to lead to the generation of ROS, potentially leading to damage of various cellular components. Iron can become integrated into the phospholipid bilayer, and act to oxidize cell membrane constituents and/or participate in reactions leading to the generation of ROS 87, 88. The link between iron, metabolic syndrome, and Alzheimer's disease has

Impact of Heme on Adipocyte Differentiation – Adipogenesis and Obesity

The discovery by London's group in 1981 that heme is essential for the increase in pre-adipocyte differentiation and adipogenesis [12] was followed by the elegant work of the Burris group showing that synthesis and an increase of heme is associated with recruitment of ligands for REV-ERB nuclear receptors (NR1D1/2) and an increase in adipogenesis [13]. This suggests that heme metabolism plays an important role in adiposity, and the discovery of new targets in HO-1 signaling may prove useful for

HO, Inflammation, and Vascular Disease

The protective role of HO-1 and CO against inflammation occurs in many different disease models including ethanol-induced liver cell death [128]. Resveratrol both in vitro and in vivo upregulates HO-1 expression, NAD(P)H;quinone oxidoreductase 1, and γ-glutamylcysteine synthetase via activation of nuclear factor (erythroid-derived)-like 2 (NRF2) target genes. Resveratrol administered to mice fed a high-fat diet attenuated oxidative stress and improved acetylcholine-induced vasodilation. The

Impact of HO-1/HO-2 on Hypertension

The biological action of HO-1 and HO-2 gene expression suggests their capacity to participate in the regulation of renal function and blood pressure 147, 148, 149, 150, 151, 152. HO-2 deficiency contributes to a diabetes-mediated increase in superoxide anion and renal dysfunction [39]. Inhibitors of HO activity exacerbate salt-sensitive hypertension in Dahl salt-sensitive rats via inhibition of the pressure-natriuretic response [153]. Inhibition of HO activity can blunt pressure-natriuresis via

HO and the Regulation of Lipid-Mediator Signaling in Hypertension and Obesity

The CYP family of monooxygenases/epoxygenases is responsible for the formation of 20-HETE and EETs 160, 161. Upon formation, EETs are subjected to rapid hydrolysis by epoxide hydrolases and ROS (preventable by HO-1 induction) to their respective dihydroxyepoxytrienoic acids (DHETs), as well as to esterification primarily to glycerophospholipids. Vasodilatory, anti-inflammatory, and anti-apoptotic actions of EETs are well established, and it is well documented that inhibition of soluble epoxide

HO-1/HO-2 and Health Impact

Obesity is a crucial risk factor for endothelial dysfunction and the subsequent development of diabetes mellitus and vascular diseases including hypertension. Abdominal obesity is associated with insulin resistance and the pathogenesis of T2DM and hypertension, contributes to high serum levels of LDL and triglycerides but low serum levels of HDL, and leads to the development of atherosclerotic CVD 169, 170, 171. HO-1-mediated decreases in ROS and LDL levels were reported in several diabetes

Therapeutic Potential of HO-1 and Signaling Pathways

HO-1, as the only enzyme that degrades the pro-oxidant heme and generates antioxidant products, may be a beneficial target to limit the pathogenesis of obesity and diabetes and their complications (Figure 5). In diabetes, increased levels of HO-1 provide vascular cytoprotection against oxidative stress via mechanism(s) that involve improvements in mitochondrial biogenesis and function 127, 185. Cardiac mitochondrial damage, such as that seen in type 1 diabetes mellitus (TD1M), is the result of

HO-1 Genetic Polymorphism and its Impact on Atherosclerosis and CVD

Genetic polymorphism of the HMOX1 gene indicates the potential importance of HO-1 in the pathogenesis of cardiovascular and pulmonary diseases [210]. Larger (GT)n repeats in the HMOX1 gene promoter were associated with reduced HO-1 inducibility by ROS present in cigarette smoke, predisposing to the development of emphysema [210]. Patients with short (<25 GT) dinucleotide repeats in the HMOX1 gene promoter on either allele had restenosis significantly less often than patients with longer (≥25

Concluding Remarks

The pharmaceutical industry may be interested in finding novel drugs with the potential to attenuate adiposity and reprogram adipocyte stem cells to new phenotypes to express HO-1 or HO-1 downstream targets (see Outstanding Questions). A potential inducer of bilirubin and HO-1 is a peptide derived from the human biliverdin reductase protein [221]. This peptide, as well as the L-4F (APOA1 mimetic) peptide, could have a powerful effect on the induction of HO-1, with reduced of fatty liver insulin

Acknowledgments

This work was supported by National Institutes of Health (NIH) grants HL55601 and HL34300 (N.G.A.). We thank Mrs Jennifer Brown for her outstanding assistance in preparing the manuscript.

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      These new functions mostly rely on the regulation of cellular metabolism whereby alterations at the expenses of HO1 and BVR-A were associated with metabolic disorders [2,6,7]. While HO1 role in metabolic disorders has been largely investigated in vitro, in animal models and in humans [2,3], the role for BVR-A deserve further investigations. In addition, considering that BVR-A is a key regulator for HO1 induction [8–10], whether observed alterations at the expenses of HO1 may be due to alterations of BVR-A remains an open question.

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