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Protective effect of betaine against liver steatosis involves depletion of homocysteine via upregulation of betaine‐homocysteine methyltransferase (BHMT)
Author(s) -
Ahn Chul W,
Jun Doo S,
Na Jong D,
Choi Yeo J,
Kim Young C
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.691.19
Subject(s) - betaine , ampk , homocysteine , cystathionine beta synthase , chemistry , methionine , methyltransferase , phosphorylation , endocrinology , steatosis , medicine , fatty liver , amp activated protein kinase , lipogenesis , protein kinase a , biochemistry , methylation , lipid metabolism , biology , disease , amino acid , gene
Accumulation of lipids in hepatocytes plays an important role in the development of metabolic diseases. Adenosine monophosphate‐activated protein kinase (AMPK) has emerged as a potential target for intervention in hepatic fat accumulation. In this study we determined the effect of betaine, a substrate utilized in remethylation of homocysteine to methionine in the transsulfuration reactions, on the AMPK pathway and lipogenesis in liver. Male rats were fed methionine‐choline deficient diet (MCD) for 3 wk. Intake of MCD resulted in a marked accumulation of lipids in liver. Phosphorylation of AMPK, acetyl‐CoA carboxylase (ACC), sterol regulatory element binding protein (SREBP)‐1c, and liver kinase B1 (LKB1) was inhibited significantly. Betaine supplementation (1 %) prevented or reversed all the changes induced by MCD intake. The underlying mechanism of AMPK activation provided by betaine was investigated using different hepatoma cell lines. Betaine treatment enhanced phosphorylation of AMPK, SREBP‐1c, and ACC in H4IIE, but not in HepG2 cells. Betaine‐homocysteine methyltransferase (BHMT) was induced and homocysteine levels were reduced by betaine only in H4IIE cells. Homocysteine treatment decreased pAMPK, pACC, pSREBP‐1c, and pLKB1 in a dose‐dependent manner, which was all prevented by betaine. BHMT protein expression was inhibited by homocysteine and betaine reversed its inhibition in H4IIE cells. Treatment of hydroxylamine, a cystathionine β‐synthase inhibitor, resulted in a significant increment of homocysteine, while decreasing phosphorylation of AMPK, ACC, and SREBP‐1c. Metformin treatment to HepG2 cells increased phosphorylation of AMPK, ACC, and SREBP‐1c, which was suppressed by homocysteine. Taken together, the results show that the elevation of homocysteine in hepatocytes may be responsible for the inactivation of the AMPK pathway. It is strongly suggested that anti‐lipogenic activity of betaine is associated with depletion of homocysteine via upregulation of BHMT. Support or Funding Information Supported by National Research Foundation (NRF) grants (No. 2014‐R1A2A1A11052967 and No. 2009‐0083533) funded by the Ministry of Education, Science and Technology (MEST), Korea.