delta-Valerobetaine
目录号 : GC33459
Delta-Valerobetaine 是三甲胺 N-氧化物 (TMAO) 的前体。
Cas No.:6778-33-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
HepG2 |
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Preparation Method |
Tracing the oxidation of 13C16 palmitic acid in HepG2 cells to examine the effect of VB treatment on cellular mitochondrial fatty acid oxidation. |
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Reaction Conditions |
10,50 µM for 12h |
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Applications |
Delta-Valerobetaine decreased the formation of labeled acetyl-CoA by approximately 75% compared to vehicle . Addition of carnitine back to cells pretreated with delta-Valerobetaine for 12 hours restored the carnitine-dependent formation of mitochondrial acetyl-CoA . Co-treatment of delta-Valerobetaine with the addition of stable isotope-labeled palmitate decreased the formation of labeled acetyl-CoA by approximately 25% compared to vehicle. |
| Animal experiment [2]: | |
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Animal models |
germ-free (GF) mice |
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Preparation Method |
Delta-Valerobetaine is not present in the sterilized chow (Teklad) used as the control diet for GF and conventionalization experiments. The conventional chow (Labdiet), which was not autoclavable, was used as the control for conventional mouse experiments. |
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Dosage form |
10,25,50,100 mg/kg 6 weeks |
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Applications |
Delta-Valerobetaine alters carnitine shuttle metabolism in male and female mice. VB decreases circulating carnitines in mice. Delta-Valerobetaine decreases circulating and hepatic beta-hydroxybutyrate, produced from mitochondrial fatty acid oxidation during fasting. VB alters neutral lipid profiles liver, heart, and brain of male and female mice. Neutral lipids from untargeted lipidomic profiling with average fold-change greater than 2 in 100 mg/kg Delta-Valerobetaine -treated mice (n = 5 male, n = 5 female) versus control (n = 5 male, n = 5 female). |
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References: [1]. Liu K H, Owens J A, Saeedi B, et al. Microbial metabolite delta-valerobetaine is a diet-dependent obesogen[J]. Nature Metabolism, 2021, 3(12): 1694-1705. | |
Delta-Valerobetaine is a precursor of trimethylamine N-oxide (TMAO) [1]. Delta-Valerobetaine, microbiome-derived metabolite, is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans[2].
Delta-Valerobetaine is absent in germ-free mice and their mitochondria but present in ex-germ-free conventionalized mice and their mitochondria. Mechanistic studies in vivo and in vitro show Delta-Valerobetaine is produced by diverse bacterial species and inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine and mitochondrial long-chain acyl-coenzyme As. delta-Valerobetaine administration to germ-free and conventional mice increases visceral fat mass and exacerbates hepatic steatosis with a western diet but not control diet. Delta-Valerobetaine provides a molecular target to understand and potentially manage microbiome-host symbiosis or dysbiosis in diet-dependent obesity. Delta-Valerobetaine is produced in the rumen from free TML that occurs ubiquitously in vegetable kingdom [3].
Delta-Valerobetaine appears to be degraded by gut microbiota, as it happens for γ-butyrobetaine. In the biochemical pathways for the production and metabolism of TMA and TMAO, compounds containing the trimethylammonium group, such as betaines, choline, carnitine, are metabolized by gut microbiota producing TMA which is absorbed and travels via the portal circulation to the liver, where it is oxidized by flavin monooxygenases (FMO1 and FMO3) to TMAO, a metabolite known to positively correlate to the occurrence of cardiovascular risks[4-7].
References:
[1]. Servillo L, et al. Ruminant meat and milk contain δ-valerobetaine, another precursor of trimethylamine N-oxide (TMAO) like γ-butyrobetaine. Food Chem. 2018 Sep 15;260:193-199
[2]. Liu K H, Owens J A, Saeedi B, et al. Microbial metabolite delta-valerobetaine is a diet-dependent obesogen[J]. Nature Metabolism, 2021, 3(12): 1694-1705.
[3]. Servillo L, Giovane A, Cautela D, et al. Where does Nε-trimethyllysine for the carnitine biosynthesis in mammals come from?[J]. PloS one, 2014, 9(1): e84589.
[4]. Wang Z, Klipfell E, Bennett B J, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease[J]. Nature, 2011, 472(7341): 57-63.
[5].Zeisel S H, Warrier M. Trimethylamine N-oxide, the microbiome, and heart and kidney disease[J]. Annual review of nutrition, 2017, 37: 157-181.
[6]. Randrianarisoa E, Lehn-Stefan A, Wang X, et al. Relationship of serum trimethylamine N-oxide (TMAO) levels with early atherosclerosis in humans[J]. Scientific reports, 2016, 6(1): 1-9.
[7]. Subramaniam S, Fletcher C. Trimethylamine N?\oxide: breathe new life[J]. British Journal of Pharmacology, 2018, 175(8): 1344-1353.
Delta-Valerobetaine 是三甲胺 N-氧化物 (TMAO) [1] 的前体。微生物组衍生的代谢物 Delta-Valerobetaine 是一种饮食依赖性致肥胖因子,随着表型肥胖而增加,并与人类的内脏脂肪组织质量相关[2]。
Delta-Valerobetaine 不存在于无菌小鼠及其线粒体中,但存在于无菌常规小鼠及其线粒体中。体内和体外的机理研究表明 Delta-Valerobetaine 由多种细菌产生,并通过减少细胞肉毒碱和线粒体长链酰基辅酶 As 来抑制线粒体脂肪酸氧化。对无菌和常规小鼠施用 delta-Valerobetaine 会增加内脏脂肪量,并在西方饮食但不控制饮食的情况下加剧肝脂肪变性。 Delta-Valerobetaine 提供了一个分子靶点来理解和潜在地管理饮食依赖性肥胖中的微生物组-宿主共生或生态失调。 Delta-Valerobetaine 在瘤胃中由游离 TML 产生,游离 TML 在植物界 [3] 中无处不在。
Delta-Valerobetaine 似乎会被肠道微生物群降解,就像 γ-butyrobetaine 一样。在 TMA 和 TMAO 的产生和代谢的生化途径中,含有三甲基铵基团的化合物,如甜菜碱、胆碱、肉碱,被产生 TMA 的肠道微生物群代谢,TMA 被吸收并通过门静脉循环进入肝脏,在那里它被黄素单加氧酶（FMO1 和 FMO3）氧化成 TMAO,这是一种已知与心血管风险的发生呈正相关的代谢物[4-7]。
| Cas No. | 6778-33-2 | SDF | |
| Canonical SMILES | C[N+](C)(C)CCCCC([O-])=O | ||
| 分子式 | C8H17NO2 | 分子量 | 159.23 |
| 溶解度 | Water : 125 mg/mL (785.03 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 6.2802 mL | 31.4011 mL | 62.8022 mL |
| 5 mM | 1.256 mL | 6.2802 mL | 12.5604 mL |
| 10 mM | 0.628 mL | 3.1401 mL | 6.2802 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Microbial metabolite delta-valerobetaine is a diet-dependent obesogen
Nat Metab2021 Dec;3(12):1694-1705.PMID: 34931082DOI: 10.1038/s42255-021-00502-8
Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome. However, the causality of changes in the microbiome-host interaction affecting energy metabolism remains controversial. Here, we show the microbiome-derived metabolite δ-valerobetaine (VB) is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans. VB is absent in germ-free mice and their mitochondria but present in ex-germ-free conventionalized mice and their mitochondria. Mechanistic studies in vivo and in vitro show VB is produced by diverse bacterial species and inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine and mitochondrial long-chain acyl-coenzyme As. VB administration to germ-free and conventional mice increases visceral fat mass and exacerbates hepatic steatosis with a western diet but not control diet. Thus, VB provides a molecular target to understand and potentially manage microbiome-host symbiosis or dysbiosis in diet-dependent obesity.
Colorectal Cancer Apoptosis Induced by Dietary δ-valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3
Int J Mol Sci2021 Jul 29;22(15):8117.PMID: 34360883DOI: 10.3390/ijms22158117
Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.
Antioxidant and Anti-Inflammatory Activities of Buffalo Milk δ-valerobetaine
J Agric Food Chem2019 Feb 13;67(6):1702-1710.PMID: 30661355DOI: 10.1021/acs.jafc.8b07166
δ-valerobetaine (δVB), a constitutive metabolite of ruminant milk, is produced in the rumen from free dietary Nε- trimethyllysine occurring ubiquitously in vegetable kingdom. The biological role of δVB is poorly known. Here, the antioxidant and anti-inflammatory potential of buffalo milk δVB was tested in vitro during high-glucose (HG)-induced endothelial damage. Results indicated that δVB (0.5 mM) ameliorated the HG cytotoxicity (0.57 ± 0.02 vs 0.41 ± 0.018 O.D. ( P < 0.01). Interestingly, buffalo milk extracts enriched with δVB showed improved significant efficacy in decreasing reactive oxygen species, lipid peroxidation, and cytokine release during HG treatment compared to milk extracts alone ( P < 0.05). It is noteworthy that δVB reduced the HG-activated inflammatory signal by modulating SIRT1 (0.96 ± 0.05 vs 0.85 ± 0.04 AU), SIRT6 (0.82 ± 0.04 vs 0.61 ± 0.03 AU), and NF-κB (0.85 ± 0.03 vs 1.23 ± 0.03 AU) ( P < 0.05). On the whole, our data show the first evidence of δVB efficacy in reducing endothelial oxidative stress and inflammation, suggesting a potential role of this betaine as a novel dietary compound with health-promoting properties.
Ruminant meat and milk contain δ-valerobetaine, another precursor of trimethylamine N-oxide (TMAO) like γ-butyrobetaine
Food Chem2018 Sep 15;260:193-199.PMID: 29699662DOI: 10.1016/j.foodchem.2018.03.114
Quaternary ammonium compounds containing N-trimethylamino moiety, such as choline derivatives and carnitine, abundant in meat and dairy products, are metabolic precursors of trimethylamine (TMA). A similar fate is reported for Nε-trimethyllysine and γ-butyrobetaine. With the aim at investigating the metabolic profile of such metabolites in most employed animal dietary sources, HPLC-ESI-MS/MS analyses on ruminant and non-ruminant milk and meat were performed. Results demonstrate, for the first time, the presence of δ-valerobetaine, occurring at levels higher than γ-butyrobetaine in all ruminant samples compared to non-ruminants. Demonstration of δ-valerobetaine metabolic origin, surprisingly, showed that it originates from rumen through the transformation of dietary Nε-trimethyllysine. These results highlight our previous findings showing the ubiquity of free Nε-trimethyllysine in vegetable kingdom. Furthermore, δ-valerobetaine, similarly to γ-butyrobetaine, can be degraded by host gut microbiota producing TMA, precursor of the proatherogenic trimethylamine N-oxide (TMAO), unveiling its possible role in the biosynthetic route of TMAO.
ROS-Mediated Apoptotic Cell Death of Human Colon Cancer LoVo Cells by Milk δ-valerobetaine
Sci Rep2020 Jun 2;10(1):8978.PMID: 32488123DOI: 10.1038/s41598-020-65865-6
δ-valerobetaine (δVB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk δVB on human colorectal cancer cells. CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3 kDa milk extract, δVB (2 mM) or milk+δVB up to 72 h. Results showed a time- and dose-dependent capability of δVB to inhibit cancer cell viability, with higher potency in LoVo cells. Treatment with milk+δVB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, δVB also increased necrosis (P < 0.01) and when used in combination with milk it improved its activity on live cell reduction (P < 0.05) and necrosis (P < 0.05). δVB-enriched milk activated caspase 3, caspase 9, Bax/Bcl-2 apoptotic pathway and reactive oxygen species (ROS) production, whereas no effects on ROS generation were observed in CCD 841 CoN cells. The altered redox homeostasis induced by milk+δVB was accompanied by upregulation of sirtuin 6 (SIRT6). SIRT6 silencing by small interfering RNA blocked autophagy and apoptosis activated by milk+δVB, unveiling the role of this sirtuin in the ROS-mediated apoptotic LoVo cell death.