Ahn Chul Won, Jun Doo Sung, Na Jong Deok, Choi Yeo Jin, Kim Young Chul
College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.
College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.
Biochem Biophys Res Commun. 2016 Aug 26;477(3):440-7. doi: 10.1016/j.bbrc.2016.06.080. Epub 2016 Jun 16.
We investigated the anti-lipogenic effect of betaine in rats fed methionine and choline-deficient diet (MCD). Intake of MCD for 3 wk resulted in a significant accumulation of hepatic lipids, which was prevented by betaine supplementation in drinking water (1%). Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), sterol regulatory element-binding protein-1c (SREBP-1c), and liver kinase B1 (LKB1) was inhibited by MCD intake, and these changes were all inhibited by betaine feeding. Meanwhile, betaine supplementation reversed the reduction of methionine and S-adenosylmethionine (SAM), and the elevation of homocysteine levels in the liver, which could be attributable to the induction of betaine-homocysteine methyltransferase (BHMT) and methionine adenosyltransferase (MAT). Different cell lines were used to clarify the role of homocysteine on activation of the AMPK pathway. Homocysteine treatment decreased pAMPK, pACC, pSREBP-1c and pLKB1 in HepG2 cells. Metformin-induced activation of AMPK was also inhibited by homocysteine. Treatment with hydroxylamine, a cystathionine β-synthase inhibitor, resulted in a reduction of pAMPK, pACC and pSREBP-1c, accompanied by an elevation of intracellular homocysteine. Betaine treatment prevented the homocysteine-induced reduction of pAMPK, pACC, pSREBP-1c and pLKB1 in H4IIE cells, but not in HepG2 cells. Also the elevation of cellular homocysteine and inhibition of protein expression of BHMT were prevented by betaine only in H4IIE cells which express BHMT. The results suggest that the beneficial effect of betaine against hepatic lipid accumulation may be attributed, at least in part, to the depletion of homocysteine via up-regulation of BHMT in hepatocytes.
我们研究了甜菜碱对喂食蛋氨酸和胆碱缺乏饮食（MCD）大鼠的抗脂肪生成作用。摄入MCD 3周导致肝脏脂质显著积累，而饮用水中补充1%的甜菜碱可预防这种积累。MCD摄入会抑制AMP激活的蛋白激酶（AMPK）、乙酰辅酶A羧化酶（ACC）、固醇调节元件结合蛋白-1c（SREBP-1c）和肝脏激酶B1（LKB1）的磷酸化，而甜菜碱喂养可抑制这些变化。同时，补充甜菜碱可逆转肝脏中蛋氨酸和S-腺苷甲硫氨酸（SAM）的减少以及同型半胱氨酸水平的升高，这可能归因于甜菜碱-同型半胱氨酸甲基转移酶（BHMT）和蛋氨酸腺苷转移酶（MAT）的诱导。使用不同的细胞系来阐明同型半胱氨酸对AMPK途径激活的作用。同型半胱氨酸处理降低了HepG2细胞中的pAMPK、pACC、pSREBP-1c和pLKB1。同型半胱氨酸也抑制了二甲双胍诱导的AMPK激活。用胱硫醚β-合酶抑制剂羟胺处理导致pAMPK、pACC和pSREBP-1c减少，同时细胞内同型半胱氨酸升高。甜菜碱处理可预防同型半胱氨酸诱导的H4IIE细胞中pAMPK、pACC、pSREBP-1c和pLKB1的减少，但对HepG2细胞无效。此外，甜菜碱仅在表达BHMT的H4IIE细胞中预防了细胞内同型半胱氨酸的升高和BHMT蛋白表达的抑制。结果表明，甜菜碱对肝脏脂质积累的有益作用可能至少部分归因于通过上调肝细胞中的BHMT来消耗同型半胱氨酸。
