Background
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].
参考文献:
[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]。
Protocol
| Cell experiment [1]: |
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Cell lines
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HepG2
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Preparation Method
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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
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10,50 μM for 12h
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Applications
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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.
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| Animal experiment [2]: |
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Animal models
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germ-free (GF) mice
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Preparation Method
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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
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10,25,50,100 mg/kg 6 weeks
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Applications
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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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参考文献:
[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.
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