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1.
Mol Cell Biochem ; 468(1-2): 169-183, 2020 May.
Article in English | MEDLINE | ID: mdl-32222880

ABSTRACT

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 (0.5 mM-2 mM) of valine for up to 48 h. 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.


Subject(s)
Amino Acids, Branched-Chain/drug effects , Insulin Resistance , Insulin/metabolism , Muscle Fibers, Skeletal/drug effects , Muscle, Skeletal/drug effects , Valine/pharmacology , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/genetics , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , Amino Acids, Branched-Chain/metabolism , Animals , Cell Line , Cell Survival/drug effects , Glycolysis/drug effects , Insulin/pharmacology , Mice , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/enzymology , Muscle, Skeletal/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics
2.
Am J Physiol Endocrinol Metab ; 316(1): E73-E85, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30422704

ABSTRACT

Increased circulating branched-chain amino acids (BCAAs) have been involved in the pathogenesis of obesity and insulin resistance (IR). However, evidence relating berberine (BBR), gut microbiota, BCAAs, and IR is limited. Here, we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet (HFD)-fed mice. BBR reorganized gut microbiota populations under both the normal chow diet (NCD) and HFD. Particularly, BBR noticeably decreased the relative abundance of BCAA-producing bacteria, including order Clostridiales; families Streptococcaceae, Clostridiaceae, and Prevotellaceae; and genera Streptococcus and Prevotella. Compared with the HFD group, predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment. Accordingly, the elevated serum BCAAs of HFD group were significantly decreased by BBR. Furthermore, the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by activation of the multienzyme branched-chain α-ketoacid dehydrogenase complex (BCKDC), whereas by inhibition of the phosphorylation state of BCKDHA (E1α subunit) and branched-chain α-ketoacid dehydrogenase kinase (BCKDK). The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes. Finally, data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs. Together, our findings clarified BBR improving IR associated not only with gut microbiota alteration in BCAA biosynthesis but also with BCAA catabolism in liver and adipose tissues.


Subject(s)
Adipose Tissue, White/drug effects , Amino Acids, Branched-Chain/drug effects , Berberine/pharmacology , Dysbiosis/metabolism , Gastrointestinal Microbiome/drug effects , Insulin Resistance , Liver/drug effects , Obesity/metabolism , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , 3T3-L1 Cells , Adipocytes/drug effects , Adipocytes/metabolism , Adipose Tissue, White/metabolism , Adult , Amino Acids, Branched-Chain/metabolism , Animals , Diabetes Mellitus/metabolism , Diet, High-Fat , Fatty Liver , Female , Gastrointestinal Microbiome/genetics , Glucose Intolerance , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Liver/metabolism , Male , Metagenomics , Mice , Middle Aged , Protein Kinases
3.
Int J Exp Pathol ; 97(3): 278-84, 2016 06.
Article in English | MEDLINE | ID: mdl-27381898

ABSTRACT

Phenylbutyrate is recommended in urea cycle disorders and liver injury to enhance nitrogen disposal by the urine. However, hypothetically there may be adverse responses to the use of phenylbutyrate in the treatment of liver disease because of its role as a histone deacetylase inhibitor and its stimulatory effect on branched-chain alpha-keto acid dehydrogenase, the rate-limiting enzyme in the catabolism of branched-chain amino acids (BCAA; valine, leucine and isoleucine). We report the effects of phenylbutyrate on liver regeneration and amino acid levels in plasma of partially hepatectomized (PH) rats. Phenylbutyrate or saline was administered at 12-h intervals to PH or laparotomized rats. Phenylbutyrate delayed the onset of liver regeneration compared to the saline-treated controls, as indicated by lower hepatic DNA specific activities 18 and 24( ) h post-PH, decreased hepatic fractional protein synthesis rates 24 h post-PH and lowered the increases in liver weights and hepatic protein and DNA contents 48 h after PH. Hepatic DNA fragmentation (a hallmark of apoptosis) was higher in the phenylbutyrate-treated animals than in controls. Phenylbutyrate decreased the glutamine and BCAA concentrations and the ratio of the BCAA to aromatic amino acids (phenylalanine and tyrosine) in the blood plasma in both hepatectomized and laparotomized animals. In conclusion, the delayed onset of liver regeneration and the decrease in BCAA/AAA ratio in blood suggest that phenylbutyrate administration may be disastrous in subjects with acute hepatic injury and BCAA supplementation is needed when phenylbutyrate is used therapeutically.


Subject(s)
Amino Acids, Branched-Chain/drug effects , Amino Acids/metabolism , Liver Regeneration/drug effects , Liver/drug effects , Phenylbutyrates/adverse effects , Ammonia/metabolism , Animals , Glutamine/metabolism , Hepatectomy/methods , Liver/metabolism , Male , Rats, Wistar
4.
Plant Physiol ; 171(1): 25-41, 2016 05.
Article in English | MEDLINE | ID: mdl-26966172

ABSTRACT

Here, we demonstrate whole-plant metabolic profiling by stable isotope labeling and combustion isotope-ratio mass spectrometry for precise quantification of assimilation, translocation, and molecular reallocation of (13)CO2 and (15)NH4NO3 The technology was applied to rice (Oryza sativa) plants at different growth stages. For adult plants, (13)CO2 labeling revealed enhanced carbon assimilation of the flag leaf from flowering to late grain-filling stage, linked to efficient translocation into the panicle. Simultaneous (13)CO2 and (15)NH4NO3 labeling with hydroponically grown seedlings was used to quantify the relative distribution of carbon and nitrogen. Two hours after labeling, assimilated carbon was mainly retained in the shoot (69%), whereas 7% entered the root and 24% was respired. Nitrogen, taken up via the root, was largely translocated into the shoot (85%). Salt-stressed seedlings showed decreased uptake and translocation of nitrogen (69%), whereas carbon metabolism was unaffected. Coupled to a gas chromatograph, labeling analysis provided enrichment of proteinogenic amino acids. This revealed significant protein synthesis in the panicle of adult plants, whereas protein biosynthesis in adult leaves was 8-fold lower than that in seedling shoots. Generally, amino acid enrichment was similar among biosynthetic families and allowed us to infer labeling dynamics of their precursors. On this basis, early and strong (13)C enrichment of Embden-Meyerhof-Parnas pathway and pentose phosphate pathway intermediates indicated high activity of these routes. Applied to mode-of-action analysis of herbicides, the approach showed severe disturbance in the synthesis of branched-chain amino acids upon treatment with imazapyr. The established technology displays a breakthrough for quantitative high-throughput plant metabolic phenotyping.


Subject(s)
High-Throughput Screening Assays/methods , Isotope Labeling/methods , Metabolome , Oryza/metabolism , Oryza/physiology , Amino Acids/metabolism , Amino Acids, Branched-Chain/drug effects , Amino Acids, Branched-Chain/metabolism , Carbon/chemistry , Carbon/metabolism , Carbon Dioxide/chemistry , Carbon Isotopes/chemistry , Carbon Isotopes/metabolism , Cell Respiration , Chromatography, Gas , Glycolysis , Herbicides/pharmacology , Hydroponics/methods , Imidazoles/pharmacology , Mass Spectrometry , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/physiology , Metabolomics , Niacin/analogs & derivatives , Niacin/pharmacology , Nitrates/chemistry , Nitrogen/chemistry , Nitrogen/metabolism , Nitrogen Isotopes/chemistry , Nitrogen Isotopes/metabolism , Oryza/drug effects , Oryza/growth & development , Pentose Phosphate Pathway , Plant Leaves/metabolism , Plant Proteins/analysis , Plant Proteins/metabolism , Plant Roots/metabolism , Plant Shoots/metabolism , Salts/metabolism , Seedlings/drug effects , Seedlings/metabolism
5.
Crit Care ; 14(3): 152, 2010.
Article in English | MEDLINE | ID: mdl-20497607

ABSTRACT

Berg and colleagues report on amino acid exchange across the human brain during endotoxin infusion. Lipopolysaccharide infusion induced a decrease in the ratio between branched chain amino acids and aromatic amino acids, increased unidirectional phenylalanine uptake, and increased net brain glutamine release. Cerebral proteolysis is suggested to play a role, but the question is whether this is the case and why this would happen.


Subject(s)
Brain/physiopathology , Glutamine/drug effects , Peptide Hydrolases/pharmacology , Sepsis/physiopathology , Amino Acids, Branched-Chain/blood , Amino Acids, Branched-Chain/drug effects , Amino Acids, Branched-Chain/metabolism , Brain/metabolism , Glutamine/blood , Glutamine/metabolism , Humans , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/pharmacology , Peptide Hydrolases/metabolism
6.
Acta Neurol Scand ; 108(1): 1-8, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12807386

ABSTRACT

OBJECTIVES: A study was conducted to examine the effect of lamotrigine (LTG) in amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS: Patients were entered in a double-blind, placebo-controlled, crossover study. None of the patients were treated with riluzole, which was not approved for treatment of ALS in Sweden when the study started. After randomization, each patient was treated with placebo or LTG 300 mg daily, followed by a washout period and a second treatment period. RESULTS: Thirty patients completed the study and were included in the analysis of the primary outcome, which was measured with clinical scales. The cerebrospinal fluid (CSF) levels of glutamate, aspartate, branched-chain amino acids and LTG were also measured. Changes for glutamate, valine and LTG were found during the progression of the disease. The clinical parameters and the levels of CSF amino acids were similar for the two treatment groups. CONCLUSION: No clinical effect of LTG on ALS progression could be found.


Subject(s)
Amino Acids, Branched-Chain/cerebrospinal fluid , Amino Acids, Branched-Chain/drug effects , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Amyotrophic Lateral Sclerosis/drug therapy , Aspartic Acid/cerebrospinal fluid , Aspartic Acid/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Antagonists/therapeutic use , Glutamic Acid/cerebrospinal fluid , Glutamic Acid/drug effects , Triazines/pharmacology , Triazines/therapeutic use , Adult , Aged , Amyotrophic Lateral Sclerosis/physiopathology , Cross-Over Studies , Double-Blind Method , Excitatory Amino Acid Antagonists/cerebrospinal fluid , Female , Humans , Lamotrigine , Male , Middle Aged , Outcome Assessment, Health Care , Triazines/cerebrospinal fluid
7.
Hepatogastroenterology ; 39(5): 451-4, 1992 Oct.
Article in English | MEDLINE | ID: mdl-1459531

ABSTRACT

Cirrhosis of the liver is typically accompanied by low plasma levels of the three branched chain amino acids (BCAA). These patients also demonstrate increased concentrations of several hormones such as insulin, glucagon and catecholamines. Catecholamines have been shown to influence the plasma levels of amino acids in healthy subjects and diabetics. In the present study, amino acid concentrations were investigated before and up to 3 hours after beta blockade (Inderal, 40-80 mg, n = 10) or fasting (n = 8) in cirrhotic patients. In the basal state the patients had low levels of all three BCAA, as compared with healthy subjects. Norepinephrine was more than 3 times as high in the patients (3.65 +/- 0.6 vs. 0.84 +/- 0.08 nmol/l, p < 0.01) while epinephrine was only slightly raised (0.43 +/- 0.1 vs. 0.25 +/- 0.06 nmol/l, NS). Significant correlations were observed between the concentrations of norepinephrine and individual as well as the sum of the three BCAA (r = 0.43-0.62, p < 0.05-0.001), while no correlation was observed between the BCAAs and epinephrine or insulin. Three hours after beta blockade the concentrations of leucine (basal: 74 +/- 6, 180 min: 89 +/- 6 mumol/l, p < 0.05) and valine (basal: 110 +/- 10, 180 min: 132 +/- 11 mumol/l, p < 0.01) had increased significantly. A similar tendency was observed for isoleucine. No changes were observed after prolonged fasting. The results suggest that catecholamines, primarily norepinephrine, might contribute to the low levels of BCAA in cirrhotics.


Subject(s)
Amino Acids, Branched-Chain/drug effects , Liver Cirrhosis/blood , Propranolol/pharmacology , Adult , Aged , Amino Acids, Branched-Chain/blood , Epinephrine/blood , Female , Humans , Insulin/blood , Liver Cirrhosis/drug therapy , Male , Middle Aged , Norepinephrine/blood , Propranolol/therapeutic use
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