Abstract
Cystathionine beta synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Betaine supplementation, which can lower tHcy by stimulating homocysteine remethylation to methionine, is often given to CBS deficient patients in combination with other treatments such as methionine restriction and supplemental B-vitamins. However, the effectiveness of betaine supplementation by itself in the treatment of CBS deficiency has not been well explored. Here, we have examined the effect of a betaine supplemented diet on the Tg-I278T Cbs −/− mouse model of CBS deficiency and compared its effectiveness to our previously published data using a methionine restricted diet. Tg-I278T Cbs −/− mice on betaine, from the time of weaning until for 240 days of age, had a 40 % decrease in mean tHcy level and a 137 % increase in serum methionine levels. Betaine-treated Tg-I278T Cbs −/− mice also exhibited increased levels of betaine-dependent homocysteine methyl transferase (BHMT), increased levels of the lipogenic enzyme stearoyl-coenzyme A desaturase (SCD-1), and increased lipid droplet accumulation in the liver. Betaine supplementation largely reversed the hair loss phenotype in Tg-I278T Cbs −/− animals, but was far less effective than methionine restriction in reversing the weight-loss, fat-loss, and osteoporosis phenotypes. Surprisingly, betaine supplementation had several negative effects in control Tg-I278T Cbs +/− mice including decreased weight gain, lean mass, and bone mineral density. Our findings indicate that while betaine supplementation does have some beneficial effects, it is not as effective as methionine restriction for reversing the phenotypes associated with severe CBS deficiency in mice.
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Acknowledgments
This work was supported by grants from the Hempling Foundation for Homocystinuria Research, the NIH (CA06927 and R01GM098772), and an appropriation from the Commonwealth of Pennsylvania. We thank the Genomics and Laboratory Animal Facilities of Fox Chase Cancer Center for their assistance. We also thank Dr. Michael Tordoff and his laboratory for help using the PIXIMus II DEXA. This equipment was provided by funds awarded to the Monell Chemical Senses Center under the grant from the Pennsylvania Department of Health. The department specifically disclaims responsibility for any analyses, interpretations, or conclusions of the study.
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Communicated by: Matthias Baumgartner
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Supplementary Fig. 1
Liver pathology of RD and BSD animals. For each animal on the study, liver pathology was assessed by H and E staining. Slides were scored either positive or negative for the presence of fat droplets in a blinded fashion. Representative H and E’s are shown. The table below shows the number of positive and total animals in each group. (PDF 61 kb)
Supplementary Fig. 2
BHMT activity. Liver extracts from mice with the indicated genotype and on the indicated diets were assessed for BHMT activity as described in Methods. Activity is expressed as a percentage of the control group (Cbs+/− mice on RD). N = 6 for each group. Bars show 95 % CI (PDF 120 kb)
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Gupta, S., Wang, L. & Kruger, W.D. Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice. J Inherit Metab Dis 39, 39–46 (2016). https://doi.org/10.1007/s10545-015-9883-z
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DOI: https://doi.org/10.1007/s10545-015-9883-z