Hepatic methionine homeostasis is conserved in C57BL/6N mice on high-fat diet despite major changes in hepatic one-carbon metabolism.
Hepatic methionine homeostasis is conserved in C57BL/6N mice on high-fat diet despite major changes in hepatic one-carbon metabolism.
复制标题
DOI：
10.1371/journal.pone.0057387
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Daniel H
中科院分区：
文献类型：
--
作者：
Dahlhoff C;Desmarchelier C;Sailer M;Fürst RW;Haag A;Ulbrich SE;Hummel B;Obeid R;Geisel J;Bader BL;Daniel H
肥胖是心血管疾病、血脂异常和非酒精性脂肪性肝病(NAFLD)发展的潜在危险因素。肝脏脂肪堆积增加是NAFLD进展的一个标志，肝脏磷脂酰胆碱(PC)代谢受损可能是发病机制的核心。肝脏PC的生物合成与磷脂酰乙醇胺N-甲基转移酶的一碳代谢有关，是极低密度脂蛋白颗粒输出肝脏脂质的重要途径。在这里，我们通过分析基因表达、蛋白质水平、代谢物浓度和核表观遗传过程的变化，评估了高脂(HF)饮食和NAFLD状态对肝脏甲基消耗和C1代谢的影响。在HF饮食诱导的肥胖小鼠的肝脏中，观察到胱硫氨酸β-合成酶显着下调，甜菜碱-同型半胱氨酸甲基转移酶表达增加。体外实验显示，在PPARα激动剂WY14,643刺激的肝癌细胞中，CBS mRNA的表达显著降低。此外，代谢物测量发现，与对照组相比，服用HF饮食的小鼠肝脏胱硫氨酸和L-α-氨基-正丁酸酯浓度降低，肝脏甜菜碱浓度降低，但蛋氨酸循环中没有代谢产物变化。此外，我们检测到肝组织中从头DNA甲基转移酶3b的基因表达减弱，但对肝脏全基因组DNA甲基化或肝脏CBS启动子区域的DNA甲基化没有影响。我们的数据表明，HF饮食诱导了PPARα介导的肝脏跨硫途径关键酶的下调，并上调了小鼠BHMT的表达，以适应增强的饮食脂肪加工，同时保留必要的氨基酸蛋氨酸。
Obesity is an underlying risk factor in the development of cardiovascular disease, dyslipidemia and non-alcoholic fatty liver disease (NAFLD). Increased hepatic lipid accumulation is a hallmark in the progression of NAFLD and impairments in liver phosphatidylcholine (PC) metabolism may be central to the pathogenesis. Hepatic PC biosynthesis, which is linked to the one-carbon (C1) metabolism by phosphatidylethanolamine N-methyltransferase, is known to be important for hepatic lipid export by VLDL particles. Here, we assessed the influence of a high-fat (HF) diet and NAFLD status in mice on hepatic methyl-group expenditure and C1-metabolism by analyzing changes in gene expression, protein levels, metabolite concentrations, and nuclear epigenetic processes. In livers from HF diet induced obese mice a significant downregulation of cystathionine β-synthase (CBS) and an increased betaine-homocysteine methyltransferase (BHMT) expression were observed. Experiments in vitro, using hepatoma cells stimulated with peroxisome proliferator activated receptor alpha (PPARα) agonist WY14,643, revealed a significantly reduced Cbs mRNA expression. Moreover, metabolite measurements identified decreased hepatic cystathionine and L-α-amino-n-butyrate concentrations as part of the transsulfuration pathway and reduced hepatic betaine concentrations, but no metabolite changes in the methionine cycle in HF diet fed mice compared to controls. Furthermore, we detected diminished hepatic gene expression of de novo DNA methyltransferase 3b but no effects on hepatic global genomic DNA methylation or hepatic DNA methylation in the Cbs promoter region upon HF diet. Our data suggest that HF diet induces a PPARα-mediated downregulation of key enzymes in the hepatic transsulfuration pathway and upregulates BHMT expression in mice to accommodate to enhanced dietary fat processing while preserving the essential amino acid methionine.
登录
查看更多内容
影响因子：
9
作者：
HONG, RW;ROUNDS, JD;WILMORE, DW
通讯作者：
WILMORE, DW
DOI：
10.1016/j.jsbmb.2012.01.009
发表时间：
2012-05-01
影响因子：
4.1
作者：
Fuerst, Rainer W.;Kliem, Heike;Ulbrich, Susanne E.
通讯作者：
Ulbrich, Susanne E.
影响因子：
3.9
作者：
Loenen, WAM
通讯作者：
Loenen, WAM
影响因子：
9.3
作者：
Holm, PI;Ueland, PM;Lien, EA
通讯作者：
Lien, EA
影响因子：
3.7
作者：
Karimi, Mohsen;Johansson, Sofia;Ekstrom, Tomas J.
通讯作者：
Ekstrom, Tomas J.