Gluconeogenesis, a pathway for glucose synthesis from non-carbohydrate substances, begins with the synthesis of oxaloacetate (OA) from pyruvate and intermediates of citric acid cycle in hepatocyte mitochondria. The traditional view is that OA does not cross the mitochondrial membrane and must be shuttled to the cytosol, where most enzymes involved in gluconeogenesis are compartmentalized, in the form of malate. Thus, the possibility of transporting OA in the form of aspartate has been ignored. In the article is shown that malate supply to the cytosol increases only when fatty acid oxidation in the liver is activated, such as during starvation or untreated diabetes. Alternatively, aspartate synthesized from OA by mitochondrial aspartate aminotransferase (AST) is transported to the cytosol in exchange for glutamate via the aspartate-glutamate carrier 2 (AGC2). If the main substrate for gluconeogenesis is an amino acid, aspartate is converted to OA via urea cycle, therefore, ammonia detoxification and gluconeogenesis are simultaneously activated. If the main substrate is lactate, OA is synthesized by cytosolic AST, glutamate is transported to the mitochondria through AGC2, and nitrogen is not lost. It is concluded that, compared to malate, aspartate is a more suitable form of OA transport from the mitochondria for gluconeogenesis.
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.
AIMS: Upregulation of ketone body (β-hydroxybutyrate, βHB) utilization has been documented in human end-stage heart failure (HF), but is unclear if this is due to intrinsic cardiac metabolic remodeling or a HF-related catabolic state. This study sought to evaluate the maximal ketone body utilization capacity and its determinants in controls and in patients with moderate HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: 19 HFrEF patients and 9 controls underwent sampling from the arterial circulation (A) and coronary sinus (CS) to measure transmyocardial extraction of energy-providing substrates and oxygen. In a separate experiment, measurements were performed 80-min after oral administration of 25 g of ketone ester (KE, (R)-3-hydroxybutyl(R)-3-hydroxybutyrate) drink in 11 HFrEF and 6 control subjects. There were no statistically significant differences in fasting substrate levels and fractional extractions between HF and controls. Administration of KE increased βHB by 12.9-fold, revealing an increased ability to utilize ketones in HFrEF as compared to controls (fractional extraction, FE%: 52 vs 39%, p = 0.035). βHB FE% correlated directly with βHB myocardial delivery (r = 0.90), LV mass (r = 0.56), LV diameter (r = 0.65) and inversely with LV EF (-0.59) (all p < 0.05). βHB FE% positively correlated with lactate FE% (p < 0.01), but not with FFA or glucose FE%, arguing against substrate competition. CONCLUSIONS: Acute nutritional ketosis enhances βHB extraction in patients with HFrEF compared to controls, and this enhancement correlates with degree of cardiac dysfunction and remodeling. Data suggest that subclinical metabolic remodeling occurs early in HF progression. Further studies are needed to determine whether exogenous ketones may have a potential therapeutic role.
- MeSH
- energetický metabolismus účinky léků MeSH
- estery aplikace a dávkování MeSH
- ketolátky metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- myokard metabolismus MeSH
- omezení příjmu potravy krev MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční selhání metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hypertensive disorders in pregnancy are a worldwide health problem for women and their infants complicating up to 10% of pregnancies and associated with increased maternal and neonatal morbidity and mortality. In Europe, 2.3-3% of pregnancies are complicated by preeclampsia. Gestational diabetes, obesity, no previous or multiple births, maternal age less than 20 or greater than 35years old and thrombophilia can be some of the possible factors related to increased risk for hypertension in pregnancy. Complications of hypertension during pregnancy affect both mothers and their infants. Ambulatory blood pressure monitoring helps to distinguish true hypertension from the white coat as pregnant women with office abnormal values may have normal out of office blood pressure. Imbalance between proangiogenic and antiangiogenic factors in placenta may lead to endothelial dysfunction, vasoconstriction, activation of the coagulation system, and hemolysis. Carotid intima-media thickness, pulse wave velocity, augmentation index, and arterial wall tension were found to be significantly increased in women with preeclampsia compared to normotensive pregnant women. Uterine artery Doppler and serum biomarkers can be used to evaluate the probability of hypertension and complications during pregnancy, but further research in the field is needed. Lately, micro ribonucleic acids have also been the focus of research as potential biomarkers.
- MeSH
- ambulantní monitorování krevního tlaku MeSH
- biologické markery krev MeSH
- hypertenze indukovaná těhotenstvím * diagnóza epidemiologie patofyziologie terapie MeSH
- kardiovaskulární komplikace v těhotenství krev epidemiologie etiologie MeSH
- krevní tlak fyziologie MeSH
- lidé MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- apolipoprotein C-III metabolismus MeSH
- dítě MeSH
- dospělí MeSH
- glykogenóza typu III metabolismus MeSH
- glykogenóza metabolismus MeSH
- glykosylace MeSH
- isoelektrická fokusace MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- transferin metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND AND AIMS: A subset of obese individuals lacks cardiometabolic impairment. We aimed to analyze hormonal profiles of insulin-sensitive obese (ISO) and insulin-resistant obese (IRO) adolescents and determine hormonal predictors of homeostasis model of insulin resistance (HOMA-IR). MATERIALS AND METHODS: A threshold of 3.16 of HOMA-IR was used to classify ISO (<3.16) IRO (≥3.16). In 702 individuals aged 13-18years (55.8% girls) anthropometric and laboratory [blood glucose, insulin, thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), sex hormone-binding globulin (SHBG), steroid hormones, luteinizing hormone, follicle stimulating hormone, prolactin, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like-peptide 1glucagon, leptin, resistin, visfatin, leptin, adiponectin and adipsin] assessments were performed. Orthogonal projections to latent structures and Mann-Whitney tests with Bonferroni correction were applied for statistical analysis. RESULTS: 52.6% girls and 42.9% boys were insulin sensitive. In the predictive model of HOMA-IR thyroid function tests, adiponectin, ghrelin and leptin concentrations played an important role in both genders. Prolactin, testosterone and glucagon contributed to the model only in boys, while progesterone and dehydroepiandrosterone sulfate levels only in girls. After Bonferroni correction levels of leptin, adiponectin, leptin/adiponectin ratio, SHBG and fT4/TSH ratio in both genders, testosterone and glucagon levels in boys and levels of TSH and fT3 in girls were related to insulin sensitivity. CONCLUSION: Metabolic health defined by HOMA-IR is partly predicted by various hormones. Some of them are gender specific. Free T4/TSH and leptin/adiponectin ratios are related to insulin sensitivity in both genders.
- MeSH
- biologické modely MeSH
- homeostáza MeSH
- hormony krev MeSH
- index tělesné hmotnosti MeSH
- inzulinová rezistence * MeSH
- lidé MeSH
- mladiství MeSH
- obezita patofyziologie MeSH
- pohlavní dimorfismus MeSH
- prediktivní hodnota testů MeSH
- tělesná hmotnost MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Acute alcohol consumption can induce hypertriglyceridemia. Such an effect could be explained in part by the influence of alcohol on lipoprotein lipase (LPL) - the key enzyme responsible for triglyceride hydrolysis in circulation. Therefore, we have studied the effects of acute moderate alcohol consumption on LPL activity and on the concentrations of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4), which are known to inhibit LPL. METHODS: Two experiments were carried out in 8 healthy volunteers. They received 25 g of alcohol (vodka) in one experiment and water in the other (control). The in vivo function of LPL was estimated using intravenous fat tolerance tests (IVFTT) carried out before, 2 and 4 hours after alcohol administration. At the end of each experiment, LPL activity and mass were measured in post-heparin plasma (PHP). The concentrations of ANGPTL3 and ANGPTL4 in blood were measured before alcohol consumption and at the end of the experiments. RESULTS: LPL activity, as estimated using the IVFTT, was reduced by 25% and 24% two and four hours after the administration of alcohol, respectively, and was not affected in the control experiment. At the end of the experiment, LPL activity in PHP was 23% lower after alcohol consumption than in the controls. The concentrations of ANGPTL3 and ANGPTL4 had dropped to 67% and 86% of baseline values, respectively, at 280 min after alcohol consumption. These levels were not affected in the control experiment. The levels of ANGPTL4 but not those of ANGPTL3 were increased in PHP compared to both baseline values and values at 280 min. CONCLUSION: The capacity for triglyceride clearance seemed to be acutely reduced by alcohol consumption and the effect persisted for several hours. The levels of LPL activity in PHP were reduced to a similar extent. This reduction in LPL activity could not be explained by the changes in the levels of ANGPTL3 or ANGPTL4, which both decreased.
OBJECTIVE: In rodents, brown (BAT) and white (WAT) adipose tissues are targets and expression sites for fibroblast growth factor-21 (FGF21). In contrast, human WAT expresses negligible levels of FGF21. We examined FGF21 expression in human BAT samples, including the induced BAT found in adult patients with pheochromocytoma, and interscapular and visceral BAT from newborns. METHODS: The expression of FGF21 and uncoupling protein-1 (UCP1, a brown adipocyte marker), was determined by quantitative real-time-PCR and immunoblotting. The transcript levels of marker genes for developmentally-programmed BAT (zinc-finger-protein of the cerebellum-1, ZIC1) and inducible-BAT (cluster of differentiation-137, CD137) were also determined. RESULTS: FGF21 and UCP1 are significantly expressed in visceral adipose tissue from pheochromocytoma patients, but not in visceral fat from healthy individuals. In neonates, FGF21 and UCP1 are both expressed in visceral and interscapular fat, and their expression levels show a significant positive correlation. Marker gene expression profiles suggest that inducible BAT is present in visceral fat from pheochromocytoma patients and neonates, whereas developmentally-programmed BAT is present in neonatal interscapular fat. CONCLUSIONS: Human BAT, but not WAT, expresses FGF21. The expression of FGF21 is especially high in inducible, also called beige/brite, neonatal BAT, but it is also found in the interscapular, developmentally-programmed, BAT of neonates.
- MeSH
- bílá tuková tkáň metabolismus MeSH
- dospělí MeSH
- feochromocytom genetika metabolismus MeSH
- fibroblastové růstové faktory genetika metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- hnědé tukové buňky metabolismus MeSH
- iontové kanály genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- ligand 4-1BB genetika metabolismus MeSH
- mitochondriální proteiny genetika metabolismus MeSH
- nádory nadledvin genetika metabolismus MeSH
- novorozenec MeSH
- senioři MeSH
- transkripční faktory genetika metabolismus MeSH
- transkriptom genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- genotyp MeSH
- ghrelin * genetika MeSH
- index tělesné hmotnosti * MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- obezita epidemiologie genetika MeSH
- poměr pasu a boků * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
The role of hormone replacement therapy and estrogen replacement therapy (ERT) in cardiovascular disease prevention has not been unambiguously defined yet. The metabolic effects of estrogens may vary depending upon the route of administration. Therefore, we compared the impact of unopposed oral or transdermal ERT on plasma lipids and lipoproteins in 41 hysterectomized women. This was an open-label, randomized, crossover study (with 2 treatments and 2 periods). The 41 hysterectomized women were randomized to receive oral or transdermal 17beta-estradiol in the first or second of two 12-week study periods. Plasma lipid and lipoprotein levels were assayed before and after each treatment using standard automated methods. Lipid content of lipoprotein subclasses was assessed by sequential ultracentrifugation. The atherogenic index of plasma (AIP) was calculated as log(triglyceride [TG]/high-density lipoprotein [HDL] cholesterol). The difference between the 2 forms of administration was tested using a linear mixed model. The change from baseline for each of the forms was tested using paired t test. Oral ERT resulted in a significant increase in HDL cholesterol and apolipoprotein A-I levels, whereas it significantly decreased total and low-density lipoprotein (LDL) cholesterol and increased TG concentrations. Transdermal ERT had no such effect. Oral ERT led to a significant TG enrichment of HDL (0.19 +/- 0.06 vs 0.27 +/- 0.07 mmol/L, P < .001) and LDL particles (0.23 +/- 0.08 vs 0.26 +/- 0.10 mmol/L, P < .001) compared with baseline, whereas transdermal therapy did not have any effect on lipoprotein subclasses composition. The difference between the 2 treatments was statistically significant for HDL-TG and LDL-TG (0.27 +/- 0.07 vs 0.19 +/- 0.05 mmol/L, P < .001 and 0.26 +/- 0.10 vs 0.22 +/- 0.07 mmol/L, P< .001, respectively). The transdermal but not oral ERT significantly reduced the AIP compared with baseline (-0.17 +/- 0.26 vs -0.23 +/- 0.25, P = .023), making the difference between the therapies statistically significant (-0.23 +/- 0.25 vs -0.18 +/- 0.22, P = .017). Oral administration of ERT resulted in TG enrichment of LDL and HDL particles. Transdermal ERT did not change the composition of the lipoproteins and produced a significant improvement of AIP. Compared with transdermal ERT, orally administered ERT changes negatively the composition of plasma lipoproteins.
- MeSH
- aplikace kožní MeSH
- aplikace orální MeSH
- estradiol aplikace a dávkování MeSH
- estrogenní substituční terapie metody MeSH
- financování organizované MeSH
- HDL-cholesterol krev MeSH
- hysterektomie MeSH
- klinické křížové studie MeSH
- LDL-cholesterol krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipoproteiny krev MeSH
- ovarektomie MeSH
- triglyceridy krev MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
