RESUMEN
Cystathionine beta-synthase-deficient homocystinuria (HCU) is a life-threatening disorder of sulfur metabolism. HCU can be treated by using betaine to lower tissue and plasma levels of homocysteine (Hcy). Here, we show that mice with severely elevated Hcy and potentially deficient in the folate species tetrahydrofolate (THF) exhibit a very limited response to betaine indicating that THF plays a critical role in treatment efficacy. Analysis of a mouse model of HCU revealed a 10-fold increase in hepatic levels of 5-methyl -THF and a 30-fold accumulation of formiminoglutamic acid, consistent with a paucity of THF. Neither of these metabolite accumulations were reversed or ameliorated by betaine treatment. Hepatic expression of the THF-generating enzyme dihydrofolate reductase (DHFR) was significantly repressed in HCU mice and expression was not increased by betaine treatment but appears to be sensitive to cellular redox status. Expression of the DHFR reaction partner thymidylate synthase was also repressed and metabolomic analysis detected widespread alteration of hepatic histidine and glutamine metabolism. Many individuals with HCU exhibit endothelial dysfunction. DHFR plays a key role in nitric oxide (NO) generation due to its role in regenerating oxidized tetrahydrobiopterin, and we observed a significant decrease in plasma NOx (NO2 + NO3) levels in HCU mice. Additional impairment of NO generation may also come from the HCU-mediated induction of the 20-hydroxyeicosatetraenoic acid generating cytochrome CYP4A. Collectively, our data shows that HCU induces dysfunctional one-carbon metabolism with the potential to both impair betaine treatment and contribute to multiple aspects of pathogenesis in this disease.
Asunto(s)
Homocistinuria , Hígado , Oxidación-Reducción , Tetrahidrofolato Deshidrogenasa , Tetrahidrofolatos , Animales , Homocistinuria/metabolismo , Homocistinuria/tratamiento farmacológico , Homocistinuria/genética , Ratones , Tetrahidrofolatos/metabolismo , Hígado/metabolismo , Tetrahidrofolato Deshidrogenasa/metabolismo , Tetrahidrofolato Deshidrogenasa/genética , Betaína/metabolismo , Betaína/farmacología , Homocisteína/metabolismo , Ratones Endogámicos C57BL , Cistationina betasintasa/metabolismo , Cistationina betasintasa/genética , Carbono/metabolismo , Masculino , Ácido Fólico/metabolismo , FemeninoRESUMEN
PURPOSE: Adiponectin is a potent uterine tocolytic that decreases with gestational age, suggesting it could be a maternal metabolic quiescence factor. Maternal stress can influence preterm birth risk, and adiponectin levels may be stress-responsive. We characterized associations between adiponectin and glucocorticoids with preterm birth and modeled their predictive utility. We hypothesized maternal plasma adiponectin and cortisol are inversely related and lower adiponectin and higher cortisol associate with preterm birth. METHODS: We performed a nested case-control study using biobanked fasting maternal plasma. We included low-risk singleton pregnancies, and matched 1:3 (16 preterm, 46 term). We quantified total, high (HMW), and low molecular weight (LMW) adiponectin using ELISA. We validated an HPLC-MS/MS serum assay for use in plasma, to simultaneously measure cortisol, cortisone, and five related steroid hormones. We used linear/logistic regression to compare group means and machine learning for predictive modeling. RESULTS: The preterm group had lower mean LMW adiponectin (3.07 µg/mL vs. 3.81 µg/mL at 15w0d, P=0.045) and higher mean cortisone (34.4 ng/mL vs. 29.0 ng/mL at 15w0d, P=0.031). The preterm group had lower cortisol-to-cortisone and lower LMW adiponectin-to-cortisol ratios. We found HMW adiponectin, cortisol-to-cortisone ratio, cortisone, maternal height, age, and pre-pregnancy BMI most strongly predicted preterm birth (AUROC=0.8167). In secondary analyses, we assessed biomarker associations with maternal self-reported psychosocial stress. Lower perceived stress associated with a steeper change in cortisone in the term group. CONCLUSION: Overall, metabolic and stress biomarkers associated with preterm birth in this healthy cohort. We identify a possible mechanistic link between maternal stress and metabolism for pregnancy maintenance.