Ammonia-lowering activities and carbamoyl phosphate synthetase 1 (Cps1) induction mechanism of a natural flavonoid.
Ammonia-lowering activities and carbamoyl phosphate synthetase 1 (Cps1) induction mechanism of a natural flavonoid.
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DOI：
10.1186/s12986-015-0020-7
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发表时间：
2015
影响因子：
4.5
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Nohara K;Shin Y;Park N;Jeong K;He B;Koike N;Yoo SH;Chen Z
氨解毒对于生理健康至关重要，肝脏中的尿素循环在氨处理中起着主要作用。川陈皮素 (NOB) 是一种天然膳食类黄酮，已知具有多种生理功效。在当前的研究中，我们研究了 NOB 在氨控制中的潜在作用及其潜在的细胞机制。 C57BL/6 小鼠用普通食物 (RC)、高脂肪 (HFD) 或高蛋白饮食 (HPD) 喂养，并用载体或 NOB 治疗。测量血清和/或尿液中氨和尿素的水平。在昼夜节律周期中测定编码尿素循环酶和 C/EBP 转录因子的基因的肝脏表达。进行荧光素酶报告基因测定以研究 CCAAT 共有元件对氨基甲酰磷酸合成酶 (Cps1) 基因启动子的功能。利用生物钟缺陷小鼠突变体 ClockΔ19/Δ19 来检查生物钟在介导 Cps1 的 NOB 诱导中的必要作用。 NOB 能够降低喂食 RC、HFD 或 HPD 的小鼠的血清氨水平。与RC相比，HFD抑制了编码尿素循环限速酶的Cps1的mRNA和蛋白表达。有趣的是，NOB 在 HFD 条件下通过诱导转录因子 C/EBPα 和 C/EBPβ 来恢复 CPS1 蛋白水平。相对于 RC，其他尿素循环基因的表达也被 HFD 降低，并被 NOB 不同程度地恢复，这与 Cps1 启动子报告基因分析相结合，表明 NOB 共诱导尿素循环基因存在依赖于 C/EBP 的机制。相比之下，相对于 RC，HPD 显着提高了 CPS1 水平，但 NOB 并未显着进一步富集 CPS1。使用昼夜节律小鼠突变体 ClockΔ19/Δ19，我们还表明，在 HFD 条件下，NOB 诱导 CPS1 需要一个功能性昼夜节律时钟，已知可调节 C/EBP 和 CPS1 表达。 NOB 是一种膳食类黄酮，在不同饮食中的氨控制中表现出广泛的活性，并通过 C/EBP 和时钟依赖性调节机制调节尿素循环功能。本文的在线版本 (doi:10.1186/s12986-015-0020-7) 包含补充材料，可供授权用户使用。
Ammonia detoxification is essential for physiological well-being, and the urea cycle in liver plays a predominant role in ammonia disposal. Nobiletin (NOB), a natural dietary flavonoid, is known to exhibit various physiological efficacies. In the current study, we investigated a potential role of NOB in ammonia control and the underlying cellular mechanism. C57BL/6 mice were fed with regular chow (RC), high-fat (HFD) or high-protein diet (HPD) and treated with either vehicle or NOB. Serum and/or urine levels of ammonia and urea were measured. Liver expression of genes encoding urea cycle enzymes and C/EBP transcription factors was determined over the circadian cycle. Luciferase reporter assays were carried out to investigate function of CCAAT consensus elements on the carbamoyl phosphate synthetase (Cps1) gene promoter. A circadian clock-deficient mouse mutant, ClockΔ19/Δ19, was utilized to examine a requisite role of the circadian clock in mediating NOB induction of Cps1. NOB was able to lower serum ammonia levels in mice fed with RC, HFD or HPD. Compared with RC, HFD repressed the mRNA and protein expression of Cps1, encoding the rate-limiting enzyme of the urea cycle. Interestingly, NOB rescued CPS1 protein levels under the HFD condition via induction of the transcription factors C/EBPα and C/EBPβ. Expression of other urea cycle genes was also decreased by HFD relative to RC and again restored by NOB to varying degrees, which, in conjunction with Cps1 promoter reporter analysis, suggested a C/EBP-dependent mechanism for the co-induction of urea cycle genes by NOB. In comparison, HPD markedly increased CPS1 levels relative to RC, yet NOB did not further enrich CPS1 to a significant extent. Using the circadian mouse mutant ClockΔ19/Δ19, we also showed that a functional circadian clock, known to modulate C/EBP and CPS1 expression, was required for NOB induction of CPS1 under the HFD condition. NOB, a dietary flavonoid, exhibits a broad activity in ammonia control across varying diets, and regulates urea cycle function via C/EBP-and clock-dependent regulatory mechanisms. The online version of this article (doi:10.1186/s12986-015-0020-7) contains supplementary material, which is available to authorized users.
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影响因子：
5.3
作者：
Christoffels, VM;Grange, T;Lamers, WH
通讯作者：
Lamers, WH
影响因子：
4.8
作者：
Corvi, MM;Soltys, CLM;Berthiaume, LG
通讯作者：
Berthiaume, LG
影响因子：
3.9
作者：
Haeberle, Johannes
通讯作者：
Haeberle, Johannes
影响因子：
4.8
作者：
Kimura, T;Christoffels, VM;Takiguchi, M
通讯作者：
Takiguchi, M
昼夜节律的代谢和能量学的融合。
DOI：
10.1126/science.1195027
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bass J;Takahashi JS
通讯作者：
Takahashi JS