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Frontiers in Pharmacology 2021Liver plays a pivotal role in maintaining blood glucose levels through complex processes which involve the disposal, storage, and endogenous production of this... (Review)
Review
Liver plays a pivotal role in maintaining blood glucose levels through complex processes which involve the disposal, storage, and endogenous production of this carbohydrate. Insulin is the hormone responsible for regulating hepatic glucose production and glucose storage as glycogen, thus abnormalities in its function lead to hyperglycemia in obese or diabetic patients because of higher production rates and lower capacity to store glucose. In this context, two different but complementary therapeutic approaches can be highlighted to avoid the hyperglycemia generated by the hepatic insulin resistance: 1) enhancing insulin function by inhibiting the protein tyrosine phosphatase 1B, one of the main enzymes that disrupt the insulin signal, and 2) direct regulation of key enzymes involved in hepatic glucose production and glycogen synthesis/breakdown. It is recognized that medicinal plants are a valuable source of molecules with special properties and a wide range of scaffolds that can improve hepatic glucose metabolism. Some molecules, especially phenolic compounds and terpenoids, exhibit a powerful inhibitory capacity on protein tyrosine phosphatase 1B and decrease the expression or activity of the key enzymes involved in the gluconeogenic pathway, such as phosphoenolpyruvate carboxykinase or glucose 6-phosphatase. This review shed light on the progress made in the past 7 years in medicinal plants capable of improving hepatic glucose homeostasis through the two proposed approaches. We suggest that Coreopsis tinctoria, Lithocarpus polystachyus, and Panax ginseng can be good candidates for developing herbal medicines or phytomedicines that target inhibition of hepatic glucose output as they can modulate the activity of PTP-1B, the expression of gluconeogenic enzymes, and the glycogen content.
PubMed: 35002743
DOI: 10.3389/fphar.2021.809994 -
Cell Proliferation Oct 2023
Topics: Humans; Liver Neoplasms; Mitochondria; Neoplasm Proteins; Cation Transport Proteins; Cyclic AMP Response Element-Binding Protein; Phosphoenolpyruvate Carboxykinase (GTP); Intracellular Signaling Peptides and Proteins
PubMed: 37435980
DOI: 10.1111/cpr.13527 -
European Journal of Nutrition Dec 2022Vitamin A is an essential nutrient with vital biological functions. The present study investigated the effect of different doses of vitamin A palmitate at different...
PURPOSE
Vitamin A is an essential nutrient with vital biological functions. The present study investigated the effect of different doses of vitamin A palmitate at different time intervals on thyroid hormones and glycemic markers.
METHODS
Male rats were administrated vitamin A palmitate at different doses (0, 0.7, 1.5, 3, 6, and 12 mg/kg, oral) and samples were collected at different time intervals of 2, 4, and 6 weeks. The levels of vitamin A, thyroid hormones (T3, T4, and TSH), deiodinases (Dio1 and Dio3), glycemic markers (blood insulin and fasting glucose levels, HOMA IR and HOMA β), retinol-binding protein 4 (RBP4) and the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were measured.
RESULTS
The findings demonstrated that long-term supplementation with high doses of vitamin A palmitate resulted in hypothyroidism (lower T3 and T4 levels and elevated TSH levels) as well as upregulation of Dio1 and Dio3 expression levels. This effect was associated with elevated glucose and insulin levels, enhanced HOMA IR, and decreased HOMA B index. In addition, prolonged vitamin A supplementation significantly increased RBP4 levels that upregulated the expression of PEPCK.
CONCLUSION
High doses of vitamin A supplementation increased the risk of hypothyroidism, modulated insulin sensitivity, and over a long period, increased the incidence of type 2 diabetes mellitus associated with oxidative stress and hepatitis.
Topics: Male; Rats; Animals; Insulin Resistance; Rats, Wistar; Vitamin A; Iodide Peroxidase; Phosphoenolpyruvate; Diabetes Mellitus, Type 2; Blood Glucose; Hypothyroidism; Glucose; Thyroid Hormones; Thyrotropin; Dietary Supplements; Insulins; Insulin
PubMed: 35804266
DOI: 10.1007/s00394-022-02945-5 -
Plant Diversity May 2023is an important medicinal and nutraceutical herb. Although the ingredients of have been identified as polysaccharides, alkaloids, amino acids, flavonoids and...
Metabolic and transcriptomic analyses elucidate a novel insight into the network for biosynthesis of carbohydrate and secondary metabolites in the stems of a medicinal orchid .
is an important medicinal and nutraceutical herb. Although the ingredients of have been identified as polysaccharides, alkaloids, amino acids, flavonoids and bibenzyls, our understanding of the metabolic pathways that regulate the synthesis of these compounds is limited. Here, we used transcriptomic and metabolic analyses to elucidate the genes and metabolites involved in the biosynthesis of carbohydrate and several secondary metabolites in the stems of . A total of 1005 metabolites and 31,745 genes were detected in the stems of . The majority of these metabolites and genes were involved in the metabolism of carbohydrates (fructose, mannose, glucose, xylulose and starch), while some were involved in the metabolism of secondary metabolites (alkaloids, β-tyrosine, ferulic acid, 4-hydroxybenzoate and chrysin). Our predicted regulatory network indicated that five genes (, , , and ) might play vital roles in the transition from carbohydrate to alkaloid synthesis. Correlation analysis identified that six genes (, , , , and ) were involved in carbohydrate metabolism, and two genes ( and ) were involved in secondary metabolite biosynthesis. Our analyses also indicated that phosphoenol-pyruvate (PEP) was a crucial bridge that connected carbohydrate to alkaloid biosynthesis. The regulatory network between carbohydrate and secondary metabolite biosynthesis established will provide important insights into the regulation of metabolites and biological systems in species.
PubMed: 37397599
DOI: 10.1016/j.pld.2022.10.004 -
Nutrients Sep 2023Dark tea has great potential in regulating glycolipid metabolism, and theabrownin (TB) is considered to be the characteristic and bioactive constituent of dark tea. This...
Dark tea has great potential in regulating glycolipid metabolism, and theabrownin (TB) is considered to be the characteristic and bioactive constituent of dark tea. This study evaluated the ability of TB1 (fermented for 7 days) and TB2 (fermented for 14 days) isolated from dark tea to reverse insulin resistance (IR) in HepG2 cells. The results indicated that TB significantly ameliorated oxidative stress by improving mitochondrial function. In addition, TB improved glycogen synthesis and glucose consumption, and inhibited gluconeogenesis and fatty acid synthesis, by regulating GSK3β (Glycogen synthase kinase 3β), G6Pase (Glucose-6-phosphatase), GCK (Glucokinase), PEPCK1 (Phosphoenolpyruvate carboxy kinase 1), SREBP-1C (sterol regulatory element-binding protein 1C), FASN (fatty acid synthase), and ACC (Acetyl-CoA carboxylase). Additionally, the results of Western blot and real-time PCR experiments demonstrated that TB modulated glucolipid metabolism through the IRS-1 (Insulin receptor substrate 1)/PI3K (phosphatidylinositol-3 kinase)/Akt (protein kinase B) signaling pathway. Treatment with the PI3K inhibitor demonstrated a favorable correlation between PI3K activation and TB action on glycolipid metabolism. Notably, we observed that TB2 had a greater effect on improving insulin resistance compared with TB1, which, due to its prolonged fermentation time, increased the degree of oxidative polymerization of TB.
PubMed: 37764646
DOI: 10.3390/nu15183862 -
Annals of Botany Nov 2023The relative contributions of C3 photosynthesis and crassulacean acid metabolism (CAM) during the earliest stages of development were investigated to assess how much...
BACKGROUND AND AIMS
The relative contributions of C3 photosynthesis and crassulacean acid metabolism (CAM) during the earliest stages of development were investigated to assess how much each might contribute to cactus pear (Opuntia ficus-indica) productivity.
METHODS
The developmental progression of C3 photosynthesis and CAM was assessed in seedlings and daughter cladodes of mature plants by titratable acidity, δ13C isotopic values and diel gas exchange measurements.
KEY RESULTS
Nocturnal acidification was observed in seedling cladodes and cotyledons at the earliest stages of development and became highly significant by 75 days of development. Seedling cotyledons showed mean δ13C values of -21.4 and -17.1 ‰ at 30 and 100 days of age, respectively. Seedling cladodes showed mean δ13C values of -19.4 and -14.5 ‰ at 30 and 100 days of age, respectively. These values are typical of CAM plants. Net CO2 assimilation was negative, then occurred in both the day and the night, with nighttime fixation becoming predominant once the primary cladode reached 5 cm in size. Emergent daughter cladodes growing on mature plants showed nocturnal titratable acidity at the earliest stages of development, which became significant when daughter cladodes were >2.5-5 cm in height. Emergent daughter cladodes showed mean δ13C values of -14.5 to -15.6 ‰, typical of CAM plants. CO2 assimilation studies revealed that net CO2 uptake was negative in daughter cladodes <12 cm in length, but then exhibited net positive CO2 assimilation in both the day and the night, with net nocturnal CO2 assimilation predominating once the daughter cladode grew larger.
CONCLUSIONS
Developing O. ficus-indica primary and daughter cladodes begin as respiring sink tissues that transition directly to performing CAM once net positive CO2 fixation is observed. Overall, these results demonstrate that CAM is the primary form of photosynthetic carbon assimilation for O. ficus-indica even at the earliest stages of seedling or daughter cladode development.
Topics: Crassulacean Acid Metabolism; Opuntia; Carbon Dioxide; Photosynthesis; Seedlings
PubMed: 37256773
DOI: 10.1093/aob/mcad070 -
Animals : An Open Access Journal From... Nov 2023Palmitic (C16:0), α-linolenic acid (C18:3n-3 ), and propionate regulate bovine pyruvate carboxylase () and phosphoenolpyruvate carboxykinase () expression in vitro. The...
Effects of an Hourly Bolus Postruminal Infusion of Flaxseed Oil or Palm Oil on Circulating Fatty Acid Concentrations and Hepatic Expression of Pyruvate Carboxylase and Phosphoenolpyruvate Carboxykinase in Dairy Cattle.
Palmitic (C16:0), α-linolenic acid (C18:3n-3 ), and propionate regulate bovine pyruvate carboxylase () and phosphoenolpyruvate carboxykinase () expression in vitro. The objective of this experiment was to determine the impact of C16:0, C18:3n-3 , propionate, and acetate postruminal infusions on hepatic and expression. We hypothesized that circulating fatty acids alter hepatic and in lactating dairy cows. Acetate, propionate, palm oil, and flaxseed oil were supplied postruminally to lactating cows ( = 4) using two 4 × 4 Latin square studies. For Experiment 1, cows were infused on an hourly basis with either a bolus of propionate, acetate, or the combination of propionate and palm oil, or acetate and palm oil, and Experiment 2 was similar, but flaxseed oil replaced palm oil. Flaxseed infusions increased plasma concentration and the molar percent of C18:3n-3 and decreased C16:0 but did not affect or expression. Palm infusions did not affect blood metabolites or the hepatic expression of or . The lack of responses to short-chain fatty acid infusions and changes in circulating long-chain fatty acids in mature cattle are not suitable models to study the effects of α-linolenic acid and propionate on bovine and expression previously observed in vitro.
PubMed: 38003190
DOI: 10.3390/ani13223572 -
Microbial Cell (Graz, Austria) May 2022Unlike other heterotrophic bacteria, (Mtb) can co-catabolize a range of carbon sources simultaneously. Evolution of Mtb within host nutrient environment allows Mtb to...
Unlike other heterotrophic bacteria, (Mtb) can co-catabolize a range of carbon sources simultaneously. Evolution of Mtb within host nutrient environment allows Mtb to consume the host's fatty acids as a main carbon source during infection. The fatty acid-induced metabolic advantage greatly contributes to Mtb's pathogenicity and virulence. Thus, the identification of key enzymes involved in Mtb's fatty acid metabolism is urgently needed to aid new drug development. Two fatty acid metabolism enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and isocitrate lyase (ICL) have been intensively studied as promising drug targets, but recently, Quinonez (mBio, doi: 10.1128/mbio.03559-21) highlighted a link between the fatty acid-induced dormancy-like state and drug tolerance. Using metabolomics profiling of a PEPCK-deficient mutant, Quinonez identified that over-accumulation of methylcitrate cycle (MCC) intermediates are phenotypically associated with enhanced drug tolerance against first- and second- line TB antibiotics. This finding was further corroborated by metabolomics and phenotypic characterization of Mtb mutants lacking either ICL or 2-methylcitrate dehydratase. Fatty acid metabolism induced drug-tolerance was also recapitulated in wildtype Mtb after treatment with authentic 2-methylisocitrate, an MCC intermediate. Together, the fatty acid-induced dormancy-like state and drug tolerance are attributed to dysregulated MCC activity.
PubMed: 35647177
DOI: 10.15698/mic2022.05.777 -
Frontiers in Bioengineering and... 2020Wild-type ATCC 13032 is known to possess two enzymes with anaplerotic (C4-directed) carboxylation activity, namely phosphoenolpyruvate carboxylase (PEPCx) and pyruvate...
Wild-type ATCC 13032 is known to possess two enzymes with anaplerotic (C4-directed) carboxylation activity, namely phosphoenolpyruvate carboxylase (PEPCx) and pyruvate carboxylase (PCx). On the other hand, C3-directed decarboxylation can be catalyzed by the three enzymes phosphoenolpyruvate carboxykinase (PEPCk), oxaloacetate decarboxylase (ODx), and malic enzyme (ME). The resulting high metabolic flexibility at the anaplerotic node compromises the unambigous determination of its carbon and energy flux in wild type. To circumvent this problem we performed a comprehensive analysis of selected single or double deletion mutants in the anaplerosis of wild-type under defined d-glucose conditions. By applying well-controlled lab-scale bioreactor experiments in combination with untargeted proteomics, quantitative metabolomics and whole-genome sequencing hitherto unknown, and sometimes counter-intuitive, genotype-phenotype relationships in these mutants could be unraveled. In comparison to the wild type the four mutants Δ Δ Δ Δ Δ, and Δ showed lowered specific growth rates and d-glucose uptake rates, underlining the importance of PCx and PEPCk activity for a balanced carbon and energy flux at the anaplerotic node. Most interestingly, the strain Δ Δ could be evolved to grow on d-glucose as the only source of carbon and energy, whereas this combination was previously considered lethal. The prevented anaplerotic carboxylation activity of PEPCx and PCx was found in the evolved strain to be compensated by an up-regulation of the glyoxylate shunt, potentially in combination with the 2-methylcitrate cycle.
PubMed: 33553115
DOI: 10.3389/fbioe.2020.602936 -
Oncogene Dec 2021Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of...
Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.
Topics: Acetylation; Acetylglucosamine; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Lung Neoplasms; Lysine Acetyltransferase 5; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphoenolpyruvate Carboxykinase (GTP); Protein Processing, Post-Translational; Trans-Activators; Tumor Cells, Cultured; Ubiquitination; Xenograft Model Antitumor Assays
PubMed: 34650217
DOI: 10.1038/s41388-021-02058-z