Valine Treatment Research Articles

Valine induces inflammation and enhanced adipogenesis in lean mice by multi-omics analysis.

The branched-chain amino acids (BCAAs) are essential to mammalian growth and development but aberrantly elevated in obesity and diabetes. Each BCAA has an independent and specific physio-biochemical effect on the host. However, the exact molecular mechanism of the detrimental effect of valine on metabolic health remains largely unknown. This study showed that for lean mice treated with valine, the hepatic lipid metabolism and adipogenesis were enhanced, and the villus height and crypt depth of the ileum were significantly increased. Transcriptome profiling on white and brown adipose tissues revealed that valine disturbed multiple signaling pathways (e.g., inflammation and fatty acid metabolism). Integrative cecal metagenome and metabolome analyses found that abundances of Bacteroidetes decreased, but Proteobacteria and Helicobacter increased, respectively; and 87 differential metabolites were enriched in several molecular pathways (e.g., inflammation and lipid and bile acid metabolism). Furthermore, abundances of two metabolites (stercobilin and 3-IAA), proteins (AMPK/pAMPK and SCD1), and inflammation and adipogenesis-related genes were validated. Valine treatment affects the intestinal microbiota and metabolite compositions, induces gut inflammation, and aggravates hepatic lipid deposition and adipogenesis. Our findings provide novel insights into and resources for further exploring the molecular mechanism and biological function of valine on lipid metabolism.

L-VALINE TREATMENT IMPROVES CELLULAR MITOCHONDRIAL FUNCTION

Abstract Branched-chain amino acids (BCAAs) are pivotal for the health of the human body. Leucine, isoleucine, and valine, which make up the BCAAs, are α-amino acids that promote skeletal muscle growth and development. Valine is one of the essential BCAAs required for the synthesis of muscle proteins and the support growth of skeletal muscles. Valine also plays a favorable role in enhancing insulin sensitivity, preserving intestinal health, and optimizing lipid metabolism. Considering the relevance of valine in promoting muscle growth and metabolism, we utilized C2C12 skeletal muscle cell line to investigate the role of valine in regulating mitochondrial functions. C2C12 cells grown on physiological normal glucose media (100mg/dL) were used for the experiments. Cells were treated with a 1.0 mM concentration of valine for 24 h. The effect of valine treatment on gene expression of important mitochondrial-related genes such as PGC-1α, and PGC-1β and mitofusin (MFN1, MFN), and mitochondrial fission 1 (Fis 1) was determined. Further, Oroboros oxygraph-O2K high-resolution respirometer was used to analyze the mitochondrial respiration in the intact C2C12 cells after valine treatment. The results showed increased gene expression of PGC-1α, PGC-1β, and mitochondrial fission and fusin genes after treatment with valine. The basal respiration, leak respiration, as well as maximal capacity of mitochondrial ETC (Electron Transport Chain), were also significantly improved after valine treatment. The findings from this study enhance our understanding of valine as an important nutrient to improve mitochondrial function to drive cellular function and biological processes.

Valine-Modified PbI2 for the Growth of Pinhole-Free Lead Halide Perovskite Thin Films by Vapor–Solid Reaction

In recent years, the efficiency of perovskite solar cells (PSCs) has rapidly increased, making PSCs commercially viable and able to compete with silicon solar cells. However, the technology for large-scale production of perovskite thin films still poses a significant challenge to the commercialization of PSCs. This is mainly because the thickness of the perovskite light-absorbing film is less than 1 μm and easily produces pinholes during large-scale production, causing serious charge recombination and reducing the efficiency of the device. As a result, the efficiencies of most large-scale PSC modules are significantly lower than those of small-size devices. Vapor-reaction technology is considered a crucial method to enhance the uniformity of perovskite thin films. However, current techniques are not yet advanced enough to deposit pinhole-free perovskite thin films on a large scale. One major challenge is that lead iodide (PbI2) precursor thin films have a tendency to develop a sheet-like structure with a loose morphology, which contributes to the formation of pinholes in the perovskite film. Additionally, uncoordinated Pb2+ could be easily generated in the PbI2 film during thermal evaporation, causing an increase in trap-states in the perovskite crystal. To address this, we developed a valine treatment process in this study to change the preferred orientation of PbI2 from a sheet-like to a particle-like aggregate and obtained compact PbI2 thin films. Meanwhile, this valine vapor treatment can significantly reduce the uncoordinated Pb2+ in PbI2 films. Based on this, we successfully prepared pinhole-free perovskite thin films using a vapor–solid reaction. Perovskite films based on these valine-treated PbI2 exhibited a reduced trap density and significantly improved PSCs’ performance, with a maximum efficiency exceeding 21%. Large-area PSC mini-modules (5 cm × 5 cm) produced from the perovskite film (30 cm × 30 cm) showed uniformly distributed power conversion efficiency values exceeding 17%, with the highest value reaching 18.78%. We believe that this facile valine vapor treatment holds great potential for the large-scale production of stable and high-efficiency PSC modules.

Valine Treatment Enhances Antimicrobial Component Production in Mammary Epithelial Cells and the Milk of Lactating Goats Without Influencing the Tight Junction Barrier

The production of antimicrobial components and the formation of less-permeable tight junctions (TJs) are important in the defense system of lactating mammary glands and for safe dairy production. Valine is a branched-chain amino acid that is actively consumed in the mammary glands and promotes the production of major milk components like β-casein; additionally, branched-chain amino acids stimulate antimicrobial component production in the intestines. Therefore, we hypothesized that valine strengthens the mammary gland defense system without influencing milk production. We investigated the effects of valine in vitro using cultured mammary epithelial cells (MECs) and in vivo using the mammary glands of lactating Tokara goats. Valine treatment at 4 mM increased the secretion of S100A7 and lactoferrin as well as the intracellular concentration of β-defensin 1 and cathelicidin 7 in cultured MECs. In addition, an intravenous injection of valine increased S100A7 levels in the milk of Tokara goats without influencing milk yield and milk components (i.e., fat, protein, lactose, and solids). In contrast, valine treatment did not affect TJ barrier function either in vitro or in vivo. These findings indicate that valine enhances antimicrobial component production without influencing milk production and TJ barrier function in lactating mammary glands; thus, valine contributes to safe dairy production.

Effects of Dietary Valine Levels on Production Performance, Egg Quality, Antioxidant Capacity, Immunity, and Intestinal Amino Acid Absorption of Laying Hens during the Peak Lay Period.

Simple SummaryIn the past, many studies have been carried out to investigate the effect of dietary valine supplementation on laying hens’ production performance and egg quality. However, knowledge concerning the optimal valine requirement during the peak lay period is limited and mainly restricted to the production performance of the hens. Within this context, the present study aimed to assess the impact of dietary valine levels on production performance, egg quality, antioxidant capacity, and immunity, as well as on intestinal amino acid absorption (i.e., serum free amino acids, digestive enzymes, and amino acid transporters). Dietary valine supplementation exerts positive effects on the production performance of the laying hens by promoting amino acid nutrient uptake and utilization. However, dietary valine supplementation might inhibit the absorption of dietary protein by downregulating peptide transporter expression of the small intestine, eventually resulting in the reduction of egg quality.The present study aimed to assess the impact of dietary valine levels on layer production performance, egg quality, immunity, and intestinal amino acid absorption of laying hens during the peak lay period. For this purpose, a total of 960 33-week-old Fengda No.1 laying hens were randomly divided into five experimental groups and fed with valine at the following different levels in a feeding trial that lasted 8 weeks: 0.59, 0.64, 0.69, 0.74, and 0.79%, respectively. Productive performances were recorded throughout the whole rearing cycle and the egg quality, serum indexes, and small intestine transporters expression were assessed at the end of the experiment after slaughter (41 weeks) on 12 hens per group. Statistical analysis was conducted by one-way ANOVA followed by LSD multiple comparison tests with SPSS 20.0 (SPSS, Chicago, IL, USA). The linear and quadratic effects were tested by SPSS 20.0. Egg mass, laying rate, broken egg rate, and feed conversion ratio were significantly improved with increasing dietary valine levels. However, the egg weight, eggshell thickness, albumen height, Haugh unit, and egg yolk color were significantly decreased with increasing dietary valine levels. Serum catalase (CAT), immunoglobulin A (IgA) and IgM levels, and malondialdehyde (MDA) levels were negative responses to valine-treated laying hens. Dietary supplemented valine enhanced the trypsin activity of duodenum chime and promoted the mRNA expression levels of ATB0,+, and LAT4 in the jejunum and corresponding serum free Ile, Lys, Phe, Val, and Tyr level. However, valine treatment significantly downregulated the mRNA expression levels of PePT1, B0AT1, LAT1, and SNAT2 in the small intestines and corresponding serum free Arg, His, Met, Thr, Ala, Asp, Glu, Gly, and Ser level. Our results suggest that 0.79% valine dietary supplementation can improve production performance by promoting amino acid nutrient uptake and utilization, and suggest a supplement of 0.79% valine to diet.

Valine Supplementation Does Not Reduce Lipid Accumulation and Improve Insulin Sensitivity in Mice Fed High-Fat Diet.

Branched-chain amino acids (BCAAs), particularly leucine, were reported to decrease obesity and relevant metabolic syndrome. However, whether valine has a similar effect has rarely been investigated. In the present study, mice were assigned into four treatments (n = 10): chow diet supplemented with water (CW) or valine (CV) and high-fat diet supplemented with water (HW) or valine (HV). Valine (3%, w/v) was supplied in the drinking water. The results showed that valine treatment markedly increased serum triglyceride and insulin levels of chow diet-fed mice. The body weight, serum triglyceride level, white adipose tissue weight, and glucose and insulin intolerance were significantly elevated by valine supplementation in high-fat diet-fed mice. Metabolomics and transcriptomics showed that several genes related to fat oxidation were downregulated, and arachidonic acid and linoleic acid metabolism were altered in the HV group compared to the HW group. In conclusion, valine supplementation did not suppress lipid deposition and metabolic disorders in mice, which provides a new understanding for BCAAs in the modulation of lipid metabolism.

Mechanisms of High Concentration Valine-Mediated Inhibition of Peach Tree Shoot Growth.

The vigorous growth of the new shoots of the peach tree was not beneficial to high quality and efficient cultivation. High concentration of amino acids can inhibit plant growth, but the mechanism is not clear. In this study, we explored the regulatory effects of seven amino acids (phenylalanine, valine, leucine, isoleucine, serine, D-alanine, and proline) (10 g⋅L–1) on the growth of peach trees. The results showed that phenylalanine, valine, and proline inhibited peach seedling growth and valine has the most significant effect and it can promote the root growth of peach seedlings. Compared with paclobutrazol, valine treatment improves net photosynthetic rate and fruit quality without reducing shoot diameter or puncture strength, and it does not affect leaf morphology. Valine enhanced the expression of PpSnRK1 (sucrose non-fermenting-1-related protein kinase) and inhibited the expression of PpTOR (Target of Rapamycin) and PpS6K (Ribosomal S6 kinase). The gibberellin content was significantly reduced in the valine treatment group. The endogenous valine content of peach seedlings was increased, acetohydroxyacid synthase (AHAS, E.C. 2.2.1.6) activity was inhibited by feedback, isoleucine synthesis was decreased, the relative amounts of branched chain amino acids were unbalanced, and growth was inhibited. However, isoleucine spraying after valine treatment could increase the content of isoleucine and alleviate the inhibition of valine on the shoot growth. In conclusion, valine is environmentally friendly to inhibit the growth of new shoots of peach trees by regulating the balance of PpSnRK1 and PpTOR and the synthesis of isoleucine.

Effect of valine on myotube insulin sensitivity and metabolism with and without insulin resistance.

Population data have consistently demonstrated a correlation between circulating branched-chain amino acids (BCAA) and insulin resistance. Most recently valine catabolite, 3-hydroxyisobutyrate, has emerged as a potential cause of BCAA-mediated insulin resistance; however, it is unclear if valine independently promotes insulin resistance. It is also unclear if excess valine influences the ability of cells to degrade BCAA. Therefore, this study investigated the effect of valine on muscle insulin signaling and related metabolism in vitro. C2C12 myotubes were treated with varying concentrations (0.5mM-2mM) of valine for up to 48h. qRT-PCR and western blot were used to measure metabolic gene and protein expression, respectively. Insulin sensitivity (indicated by pAkt:Akt), metabolic gene and protein expression, and cell metabolism were also measured following valine treatment both with and without varying levels of insulin resistance. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Valine did not alter regulators of mitochondrial biogenesis or glycolysis; however, valine reduced branched-chain alpha-keto acid dehydrogenase a (Bckdha) mRNA (but not protein) expression which was exacerbated by insulin resistance. Valine treatment had no effect on pAkt:Akt following either acute or 48-h treatment, regardless of insulin stimulation or varying levels of insulin resistance. In conclusion, despite consistent population data demonstrating a relationship between circulating BCAA (and related metabolites) and insulin resistance, valine does not appear to independently alter insulin sensitivity or worsen insulin resistance in the myotube model of skeletal muscle.

Supplementation with branched-chain amino acid on the progression of cronic hepatitis

Malnourishment is a common condition of hepatic failure. Our objective was to evaluate the effect of supplementation with branched-chain amino acid (BCAA) in the diet of rats with chronic hepatitis. Liver damage was generated using carbon tetrachloride (CCl4) for ten weeks in all treatments except control. Experimental units were randomly assigned to six treatments: valine, leucine, isoleucine, three BCAA, CCl4 and control, five replicates per treatment, and three animals per experimental unit. Serum albumin concentrations were compare. Tissue injury level was histopathologically graded from zero to three looking for disturbances such as cellular infiltration, fibrosis, and vacuolization. Also, weight gain, food intake, and liver damage signs were monitored. Samples were taken at week 6, 8, and 10. When the effect of treatment was significant (p <0.05) in the analysis of variance, multiple comparisons were adjusted with Tukey-Kramer method. The dietary supplement with BCAA does not alter the progression of fibrogenesis. However, rats under valine treatment showed significantly more weight. Animals in leucine and valine treatments exhibited significantly higher food intake. No signs of liver failure were observed in any treatment. As conclusion, valine and leucine supplementation could have a positive effect in the protein imbalance present in the chronic liver disease.

3H-Thymidininkorporation nach Isoleucinlimitation in “stringent” und “relaxed” kontrollierten Stämmen vonEscherichia coli

Stringent and relaxed strains of E. coli subjected to isoleucine starvation were examined by follow-wing the incorporation of 3H-thymidine into chromosomal DNA. After valine treatment to trigger an isoleucine deprivation (p)ppGpp is synthesized in the stringent strain only. Remarkable differences in the morphology of the amino acid starved cells of the stringent and relaxed strains can be observed. Upon isoleucine limitation 3H-thymidine incorporation into DNA is reduced in both strains, but this inhibition is remarkably delayed in the relaxed strain. Our result show that the reduction of chromosomal DNA synthesis during amino acid limitation occurs also without ppGpp, but in the presence of ppGpp this process is accelerated.

3H‐Thymidininkorporation nach Isoleucinlimitation in “stringent” und “relaxed” kontrollierten Stämmen von Escherichia coli

Stringent and relaxed strains of E. coli subjected to isoleucine starvation were examined by follow-wing the incorporation of 3H-thymidine into chromosomal DNA. After valine treatment to trigger an isoleucine deprivation (p)ppGpp is synthesized in the stringent strain only. Remarkable differences in the morphology of the amino acid starved cells of the stringent and relaxed strains can be observed. Upon isoleucine limitation 3H-thymidine incorporation into DNA is reduced in both strains, but this inhibition is remarkably delayed in the relaxed strain. Our result show that the reduction of chromosomal DNA synthesis during amino acid limitation occurs also without ppGpp, but in the presence of ppGpp this process is accelerated.

Cysteine starvation, isoleucyl-tRNAIle, and the regulation of the ilvGEDA operon of Escherichia coli.

The involvement of undermodified tRNA in the regulation of the ilvGEDA operon has been investigated using Escherichia coli C6, a relA-, Cys-, Met- mutant. This strain accumulates thionucleotide-deficient or methyl-deficient tRNA when starved for cysteine or methionine, respectively. The levels of threonine deaminase, the ilvA gene product, and transaminase B, the ilvE gene product, were both lower in cysteine-starved cells, as compared with either growing or methionine-starved cultures. When cysteine was added to cysteine-starved cells, growth ensued promptly and both enzyme activities returned to control levels. Treatment of recovering cultures with valine limited growth by isoleucine limitation, but did not cause a derepression of the ilvGEDA operon. Valine treatment of nonstarved or methionine-starved cells led to the expected increase in threonine deaminase and transaminase B activities. Cysteine-starved cells slowly regained the ability to derepress the operon after 3 h of recovery in complete medium. In contrast, the induction of the lac operon was normal in cysteine-starved cultures, even in the presence of valine. The loss of derepressibility of the ilvGEDA operon was correlated with the presence of a kinetically and chromatographically altered tRNAIle in cysteine-starved cells. No changes in tRNAIle were observed after methionine starvation. Using the periodate method, we found that the charging of tRNAIle increased from the normal level of 60 to 80% or greater after starvation for cysteine. Under conditions where the ilvGEDA operon was fully derepressed in nonstarved cells, the charging of tRNAIle fell to 27%. Unexpectedly, nearly identical results were obtained with cysteine-starved cells after an identical derepression test. These results suggest that factors other than the aminoacylation state of tRNAIle may be important in the regulation of this operon. In particular, modifications to tRNA which involve cysteine may be necessary for controlling the expression of the ilvGEDA operon in E. coli.

Replication of pBR322 DNA in stringent and relaxed strains of Escherichia coli.

Synthesis of both chromosomal and plasmid (pBR322) DNA was measured in E. coli strains differing in their relA allele (relA+:CP78; relA:CP79). It was found that upon limitation of a required amino acid or after valine treatment to trigger a stringent response synthesis of pBR322 DNA was stimulated only in the relaxed strain and was inhibited in its stringent counterpart. The results suggest that replication of plasmid DNA is negatively controlled by the relA+ allele.

The functional importance of increased brain tryptophan in the serotonergic response to restraint stress

The increase in brain tryptophan induced by restraint stress in rats has been shown to be prevented by prior administration of valine, 200 mg/kg (i.p.). Brain 5-hydroxytryptamine (5-HT) was not depleted, but the stress-induced increase in 5-hydroxyindoleaeetic acid (5-HIAA) was prevented. A 5-HT-mediated functional response to stress, elevated plasma corticosterone, was however significantly attenuated by valine pretreatment, but was not affected by valine treatment alone. This suggests that the increase in 5-HIAA in brain is not merely secondary to increased brain tryptophan but indicates an increase in functional 5-HT activity, which is in turn at least partly dependent on the increase in brain tryptophan. Measurement of kynurenine levels in the same animals indicated an increase in synthesis in stress, but did not support the hypothesis that competition occurs between the kynurenine and 5-hydroxyindole pathways of tryptophan metabolism in brain.