Alterations in the Metabolomics of Sulfur-Containing Substances in Rat Kidneys After Betaine Intake

Abstract

선행연구에서 betaine 투여가 랫트의 간 황 함유 아미노산 대사에 영향을 미친다는 것이 보고된 바 있다. 본 연구에서는 betaine 이 신장 황 함유 아미노산의 대사에 일으키는 변화를 측정하기 위해 랫트에 2 주간 1% 의 betaine 을 식수로 공급하였다. Betaine 은 신장 내 methionine 수치를 42 % 증가시켰다. 하지만 신장 내의 betaine-homocysteine methyltranferase (BHMT) 효소 함량이나 활성에는 변화가 없었다. Homocysteine 에서 methionine 으로의 remethylation 과정에 관여하는 또 다른 효소인 methionine synthase 역시 betaine 에 의해 변화하지 않았다. Betaine 투여에 의해 S-adenosylmethionine (SAM) 이 증가하였는데 SAM 을 생성하는 효소로 알려진 methionine adenosyltransferase I/III (MAT I/III) 는 측정되지 않았으나 extrahepatic tissue 에 존재한다고 알려진 methionine adenosyltransferase II (MAT II) 는 그 발현이 증가하였다. 하지만 S-adenylhomocysteine (SAH), total homocysteine, cysteine level 그리고 cystathionine β-synthase 단백질 발현에는 betaine 투여에 의한 변화가 관찰되지 않았다. 또한 glutathione (GSH) level 이나 GSH 의 생성을 매개하는 효소인 γ-glutamylcysteine synthetase (GCS) 의 발현 역시 betaine 섭취에 의한 차이가 보이지 않았다. 한편, taurine 생성 과정의 율속인자인 cysteine dioxygenase (CDO) 는 betaine 에 의해 현저히 감소하였다. 그러나 이와는 반대로, cysteine sulfinate decarboxylase (CDC) 의 발현과 hypotaurine level 은 유의적으로 증가하였다. 이상의 결과들은 betaine 이 신장 BHMT 의 결핍에도 불구하고 신장 내 황 함유 아미노산의 대사에 유의적인 영향을 미친다는 것을 시사하며, betaine 투여에 의해 증가한 간 내 methionine 이 혈액을 통해 신장으로 공급되어 신장 내 methionine 의 양을 증가시킨 것으로 추정된다. 본 연구결과의 생리학적 및 생화학적 중요성을 밝히기 위한 추가적인 연구가 필요할 것으로 생각된다.

Previous studies from this lab examined the effect of betaine treatment on liver sulfur-amino acid metabolomics. In this study, 1% of betaine dissolved in drinking water was provided to rats for two weeks in order to measure the changes in the metabolomics of sulfur-containing substances in the kidney. In rats supplemented with betaine, renal methionine level was increased by 42%. However, the activity or protein expression of betaine-homocysteine methyltransferase (BHMT) was not affected by betaine. Methionine synthase, the other enzyme which catalyzes the remethylation of homocysteine to methionine was also unchanged in the betaine treated group. S-Adenosylmethionine (SAM) concentration was increased by betaine feeding, and the protein expression of methionine adenosyltransferase II (MAT II), the type known to be expressed in extrahepatic tissues, increased in the betaine supplemented group. However, S-adenosylhomocysteine (SAH), total homocysteine, and cysteine levels as well as protein expression of cystathionine β-synthase were not affected by betaine treatment. Renal glutathione (GSH) level and the expression of γ-glutamylcysteine synthetase (GCS), the enzyme mediating the production of GSH, were also not changed by betaine supplementation. On the other hand, the rate limiting enzyme of taurine synthesis, cysteine dioxygenase (CDO) was decreased substantially by betaine treatment. However, the activity and protein expression of cysteine sulfinate decarboxylase (CDC) and its product hypotaurine levels increased significantly. These results suggest that despite the negligible expression of BHMT in the kidney, betaine may affect the renal metabolomics of sulfur-containing substances significantly. The increase in hepatic methionine due to betaine treatment appears to account for the increased methionine level in plasma, consequently increasing renal methionine uptake, which serves as the major cause for the changes in the transsulfuration reactions in the rat kidney. Further studies need to be conducted to clarify the physiological and the biochemical significance of these findings.