Trends in Pharmacological Sciences
Feature ReviewTranslational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome
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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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