Regulation of rat hepatic α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase, a key enzyme in the tryptophan-NAD pathway, by dietary cholesterol and sterol regulatory element-binding protein-2
Regulation of rat hepatic α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase, a key enzyme in the tryptophan-NAD pathway, by dietary cholesterol and sterol regulatory element-binding protein-2
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DOI：
10.1007/s00394-013-0547-1
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发表时间：
2014-03-01
影响因子：
5
通讯作者：
Egashira, Yukari
中科院分区：
文献类型：
--
作者：
Matsuda, Hiroko;Sato, Mayumi;Egashira, Yukari
烟酸是用于治疗高脂血症的较老药物之一，高脂血症是冠心病的最大危险因素。烟酸也是辅酶烟酰胺腺嘌呤二核苷酸（NAD）的前体。在哺乳动物中，α-氨基-β-羧基粘康酸-ε-半醛脱羧酶（ACMSD）在色氨酸生物合成NAD中起关键作用。然而，ACMSD与胆固醇代谢的关系尚未得到足够的澄清。本研究以高胆固醇血症大鼠和大鼠原代肝细胞为研究对象，采用含胆固醇饲料喂养雄性Sprague-Dawley大鼠10天，诱导高胆固醇血症，观察ACMSD与胆固醇代谢的关系。测定血浆和肝脏中NAD含量及肝脏ACMSD活性。在体外研究中，采用实时荧光定量PCR和Western blotting方法，检测了胆固醇和25-羟基胆固醇或他汀类药物辛伐他汀处理的大鼠原代肝细胞中ACMSD和调节胆固醇代谢的转录因子的表达。高胆固醇血症组肝脏NAD水平显著高于对照组，肝ACMSD活性明显降低。肝脏ACMSD活性与肝脏胆固醇水平呈显著负相关。此外，在用胆固醇和25-羟基胆固醇或辛伐他汀处理的原代大鼠肝细胞中，ACMSD基因和蛋白表达受到固醇依赖性调节。这些结果首次证明ACMSD与胆固醇代谢有关，并且ACMSD基因表达可能被SREBP-2上调。
Nicotinic acid is one of the older drugs used to treat hyperlipidemia, the greatest risk factor of coronary heart disease. Nicotinic acid is also a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD). In mammals, alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) plays a key role in NAD biosynthesis from tryptophan. However, the relationship between ACMSD and cholesterol metabolism has not been clarified enough yet. The present study was performed to make clear the relationship between ACMSD and cholesterol metabolism using hypercholesterolemic rats and rat primary hepatocytes.Male Sprague-Dawley rats were fed a diet containing cholesterol for 10 days to induce hypercholesterolemia. The NAD levels in the plasma and liver and hepatic ACMSD activity were determined. In vitro study, the expression of ACMSD and the transcriptional factors that regulate cholesterol metabolism were determined using rat primary hepatocytes treated with cholesterol and 25-hydroxycholesterol or simvastatin, a statin medication, by quantitative real-time PCR analysis and Western blotting analysis.The hepatic NAD level of the hypercholesterolemic group was significantly higher than the control, and the hepatic ACMSD activity of this group was significantly suppressed. There was a significant negative correlation between the hepatic ACMSD activity and liver cholesterol levels. Additionally, in primary rat hepatocytes treated with cholesterol and 25-hydroxycholesterol or simvastatin, ACMSD gene and protein expression was subjected to sterol-dependent regulation. This gene expression changed in parallel to sterol regulatory element-binding protein (SREBP)-2 expression.These results provide the first evidence that ACMSD is associated with cholesterol metabolism, and ACMSD gene expression may be upregulated by SREBP-2.