Cystathionine β‐synthase is required for body iron homeostasis

Abstract

Cystathionine b-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS 2/2 ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up-regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBSoverexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. Conclusion: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosislike phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (HEPATOLOGY 2018;67:21-35) C ystathionine b-synthase (CBS) was first isolated in the liver by Braunstein et al.(1) in 1969. The location of the human CBS gene is on chromosome 21 (43.35-43.37 Mb).(2) CBS is a key enzyme for hydrogen sulfide (H 2 S) production from L-cysteine, in addition to cystathionine gammalyase and 3-mercaptopyruvate sulfurtransferase. (2,3) H 2 S has been implicated as the third endogenous gas transmitter, after nitric oxide and carbon monoxide, functioning in the brain as well as peripheral organs.(2,3) CBS deficiency, induced by mutation in the CBS gene, is a rare autosomal recessive disorder characterized by highly elevated levels of total plasma homocysteine.(4) Patients not treated in infancy have multisystem disorders including arterial occlusions, venous thromboembolisms, osteoporosis, intellectual disabilities, psychiatric disorders, and dislocated lenses.(4,5) Homozygous knockout mice (CBS 2/2 ) rarely survive past 4 weeks of age, (2) implying that CBS is essential for survival and development in mice. It has been demonstrated that H 2 S has a significant effect on the regulation of proinflammatory cytokines including interleukin-6 (IL-6) (6) and signal transducer and activator of transcription 3 (STAT3) activity. (7)(8)(9)(10) Abbreviations: Ad, adenovirus; BMDM, bone marrow-derived macrophage; CBS, cystathionine b-synthase; 9 (11) -dien-28-oyl] imidazole; DMT1, d...

A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis

“…Altogether, these data imply that the transsulfuration pathway mediated by CBS may interact with the homeostasis of Fe 2+ to disrupt cellular lipid peroxidation, and thus negatively regulates ferroptosis. Interestingly, a recent report indeed observed that knockout of CBS in mice could cause iron-overload and damage in liver 52 .…”

Comparative localization of cystathionine beta synthases and cystathionine gamma lyase in canine, non-human primate and human retina

“…As CBS can actively produce H 2 S in retina (Markand et al, 2013;Persa et al, 2006) and brain (Kamat et al, 2015), the age-dependent increase in CBS may link to the antioxidant activity of H 2 S in the retina (George et al, 2018;Sakamoto et al, 2014) and highlight an active role for CBS in H 2 S production compared to CSE. Another explanation for the increased levels of CBS by aging could be because its role in iron hemostasis (Zhou et al, 2018) as increased levels of iron is linked to retinal diseases (Chen et al, 2009) and iron chelation is shown to prevent iron-induced retinal degenerative diseases (Song et al, 2014). We are also interested in studying the role of CBS and CSE in age-and diseasedependent human retinal degeneration.…”

<p>A Novel Liposomal S-Propargyl-Cysteine: A Sustained Release of Hydrogen Sulfide Reducing Myocardial Fibrosis via TGF-β1/Smad Pathway</p>

“…4 Within the cardiovascular system, H 2 S production, via the catabolism of cysteine by the enzyme CSE, is reported to act as a cytoprotectant against oxidative stress and has distinct functions in inflammatory and apoptotic signaling. 5,6 Moreover, roles for H 2 S gas production in vasorelaxation, 7 the stimulation of angiogenesis, [8][9][10] and protective functions in myocardial ischemia, 11,12 atherosclerosis, 13 anemia, 14,15 hypertension, 16 hypoxia 17 and heart failure 18 have been reported.…”