Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus. Recently, natural mitochondrial genome (mtDNA) polymorphisms (haplogroups) received increasing attention in the pathophysiology of human common diseases. However, retrograde effects of mtDNA variants on such traits are difficult to study in humans. The conplastic strains represent key animal models to elucidate regulatory roles of mtDNA haplogroups on defined nuclear genome background. To analyze the relationship between mtDNA variants and cardiometabolic traits, we derived a set of rat conplastic strains (SHR-mtBN, SHR-mtF344 and SHR-mtLEW), harboring all major mtDNA haplotypes present in common inbred strains on the nuclear background of the spontaneously hypertensive rat (SHR). The BN, F344 and LEW mtDNA differ from the SHR in multiple amino acid substitutions in protein coding genes and also in variants of tRNA and rRNA genes. Different mtDNA haplotypes were found to predispose to various sets of cardiometabolic phenotypes which provided evidence for significant retrograde effects of mtDNA in the SHR. In the future, these animals could be used to decipher individual biochemical components involved in the retrograde signaling.
- MeSH
- fenotyp MeSH
- kardiovaskulární nemoci * metabolismus MeSH
- krysa rodu rattus MeSH
- mitochondriální DNA * genetika MeSH
- mitochondrie metabolismus MeSH
- potkani inbrední F344 MeSH
- potkani inbrední SHR MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Úvod: NAFLD – jaterní manifestace metabolického syndromu a nezávislý kardiovaskulární rizikový faktor, se vyskytuje u 50 % obézních a 70 % diabetiků. Poruchy metabolizmu lipidů spojené s rozvojem jaterní steatózy jsou rovněž přítomny u neobézních osob a u prediabetických stavů. Posledních studie upozorňují, že podání perorálních antidiabetik – SGLT2-inhibitorů může snižovat obsah lipidů v játrech u diabetických i nediabetických pacientů, a to nezávisle na jejich antidiabetických účincích. Přesný mechanizmus jejich vlivu na lipidový a sacharidový metabolizmus v játrech znám není. Cílem studie bylo sledovat vliv podávání SGLT2-inhibitoru – empagliflozinu u neobézního prediabetického modelu na metabolické poruchy spojené s rozvojem nealkoholické jaterní steatózy. Metodika: Metabolické účinky empagliflozinu jsme sledovali u hereditárně hypertriglyceridemických potkanů – neobézního modelu metabolického syndromu s inzulinovou rezistencí, zhoršenou glukózovou tolerancí a akumulací lipidů v játrech. Empagliflozin byl podáván 8 týdnů v dávce 10 mg/kg/den. Výsledky: Léčba empagliflozinem u prediabetického modelu vedla v játrech ke snížení akumulace jak neutrálních lipidů triacylglycerolů (-18 %; p < 0,01), tak lipotoxických intermediátů diacylglycerolů (- 39 %; p < 0,001). Koncentrace cholesterolu v játrech ovlivněny nebyly. Snížení ukládání lipidů v játrech doprovázelo významné ovlivnění relativní exprese enzymů (SCD-1, FAS) a transkripčních faktorů (SREBP1, PPAR), které se uplatňují v procesu lipogeneze. Naopak exprese genů zapojených do oxidace lipidů ovlivněny nebyly. V mechanizmu příznivého účinku empagliflozinu by se mohly uplatnit změny relativních expresí proteinů cytochromu P450, zejména zvýšení CYP2E1 a snížení CYP4A a CYP1A1. Ke snížení lipogeneze a zmírnění oxidačního stresu v játrech může přispět také zvýšená mRNA exprese transkripčního faktoru Nrf2 (p < 0,05). Empagliflozin dále snížil hladiny fetuinu-A (- 30 %; p = 0,01), důležitého hepatokinu, který může zvyšovat inzulinovou senzitivitu v játrech i periferních tkáních. Závěr: V mechanizmu příznivého účinku empagliflozinu na lipidový metabolizmus v játrech se může uplatnit snížení exprese genů zapojených do lipogeneze, změny exprese cytochromu P450 i zvýšení transkripčního faktoru Nrf2. Pozorované změny v lipidovém metabolizmu byly doprovázeny ovlivněním hladin cirkulujících hepatokinů a mohou přispívat ke zmírnění účinků NAFLD v časných stadiích rozvoje a před manifestací diabetu.
- Publikační typ
- abstrakt z konference MeSH
Increased plasma total cysteine (tCys) has been associated with obesity and metabolic syndrome in human and some animal studies but the underlying mechanisms remain unclear. In this study, we aimed at evaluating the effects of high cysteine diet administered to SHR-CRP transgenic rats, a model of metabolic syndrome and inflammation. SHR-CRP rats were fed either standard (3.2 g cystine/kg diet) or high cysteine diet (HCD, enriched with additional 4 g L-cysteine/kg diet). After 4 weeks, urine, plasma and tissue samples were collected and parameters of metabolic syndrome, sulfur metabolites and hepatic gene expression were evaluated. Rats on HCD exhibited similar body weights and weights of fat depots, reduced levels of serum insulin, and reduced oxidative stress in the liver. The HCD did not change concentrations of tCys in tissues and body fluids while taurine in tissues and body fluids, and urinary sulfate were significantly increased. In contrast, betaine levels were significantly reduced possibly compensating for taurine elevation. In summary, increased Cys intake did not induce obesity while it ameliorated insulin resistance in the SHR-CRP rats, possibly due to beneficial effects of accumulating taurine.
The mechanisms behind the cardiovascular and renal benefits of empagliflozin is not fully understood. The positive impact of the medication on cardiovascular mortality can not be solely attributed to its antidiabetic effect, with a metabolic mechanism possibly involved. To investigate the metabolic effects of empagliflozin treatment (10 mg/kg/day for 6 weeks), we used an adult male rat model with serious vascular complications associated with metabolic syndrome and prediabetes. Impaired glucose tolerance, severe albuminuria and impaired insulin sensitivity were induced by intragastric administration of methylglyoxal and high sucrose diet feeding for four months. Although empagliflozin decreased body weight, non-fasting glucose and insulin, glucagon levels remained unchanged. In addition, empagliflozin increased adiponectin levels (+40%; p < 0.01) and improved skeletal muscle insulin sensitivity. Increased non-esterified fatty acids (NEFA) in empagliflozin-treated rats is understood to generate ketone bodies. Empagliflozin increased β-hydroxybutyrate levels in serum (+66%; p < 0.05) and the myocardium (30%; p < 0.01), suggesting its possible involvement as an alternative substrate for metabolism. Empagliflozin switched substrate utilisation in the myocardium, diverting glucose oxidation to fatty acid oxidation. Representing another favorable effect, empagliflozin also contributed to decreased uric acid plasma levels (-19%; p < 0.05). In the kidney cortex, empagliflozin improved oxidative and dicarbonyl stress parameters and increased gene expression of β-hydroxybutyrate dehydrogenase, an enzyme involved in ketone body utilisation. In addition, empagliflozin decreased microalbuminuria (-27%; p < 0.01) and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion (-29%; p < 0.01). Our results reveal the important systemic metabolic effect of empagliflozin on alterations in substrate utilisation and on increased ketone body use in prediabetic rats. Improved oxidative and dicarbonyl stress and decreased uric acid are also possibly involved in the cardio- and reno-protective effects of empagliflozin.
- MeSH
- benzhydrylové sloučeniny farmakologie MeSH
- glukosa metabolismus MeSH
- glukosidy farmakologie MeSH
- inzulinová rezistence MeSH
- ketolátky metabolismus MeSH
- krysa rodu rattus MeSH
- ledviny účinky léků metabolismus MeSH
- modely nemocí na zvířatech MeSH
- ochranné látky farmakologie MeSH
- oxidační stres účinky léků MeSH
- potkani Wistar MeSH
- prediabetes farmakoterapie metabolismus MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
To study the relationship between uniparental rDNA (encoding 18S, 5.8S and 26S ribosomal RNA) silencing (nucleolar dominance) and rRNA gene dosage, we studied a recently emerged (within the last 80 years) allotetraploid Tragopogon mirus (2n=24), formed from the diploid progenitors T. dubius (2n=12, D-genome donor) and T. porrifolius (2n=12, P-genome donor). Here, we used molecular, cytogenetic and genomic approaches to analyse rRNA gene activity in two sibling T. mirus plants (33A and 33B) with widely different rRNA gene dosages. Plant 33B had ~400 rRNA genes at the D-genome locus, which is typical for T. mirus, accounting for ~25% of total rDNA. We observed characteristic expression dominance of T. dubius-origin genes in all organs. Its sister plant 33A harboured a homozygous macrodeletion that reduced the number of T. dubius-origin genes to about 70 copies (~4% of total rDNA). It showed biparental rDNA expression in root, flower and callus, but not in leaf where D-genome rDNA dominance was maintained. There was upregulation of minor rDNA variants in some tissues. The RNA polymerase I promoters of reactivated T. porrifolius-origin rRNA genes showed reduced DNA methylation, mainly at symmetrical CG and CHG nucleotide motifs. We hypothesise that active, decondensed rDNA units are most likely to be deleted via recombination. The silenced homeologs could be used as a 'first reserve' to ameliorate mutational damage and contribute to evolutionary success of polyploids. Deletion and reactivation cycles may lead to bidirectional homogenisation of rRNA arrays in the long term.
- MeSH
- genová dávka * MeSH
- geny rRNA * MeSH
- metylace DNA MeSH
- molekulární evoluce MeSH
- molekulární sekvence - údaje MeSH
- organizátor jadérka MeSH
- polyploidie MeSH
- promotorové oblasti (genetika) MeSH
- RNA ribozomální 18S genetika MeSH
- RNA ribozomální 5.8S genetika MeSH
- RNA ribozomální genetika MeSH
- rostlinné geny * MeSH
- sekvenční analýza DNA MeSH
- sekvenční delece MeSH
- Tragopogon genetika MeSH
- umlčování genů * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Publikační typ
- abstrakt z konference MeSH
BACKGROUND AND AIMS: Fatty acids are important cellular constituents that may affect many metabolic processes relevant for the development of diabetes and its complications. We showed previously that vegetarian diet leads to greater increase in metabolic clearance rate of glucose (MCR) than conventional hypocaloric diet. The aim of this secondary analysis was to explore the role of changes in fatty acid composition of serum phospholipids in diet- and exercise-induced changes in MCR in subjects with type 2 diabetes (T2D). METHODS: Subjects with T2D (n=74) were randomly assigned into a vegetarian group (VG, n=37) following vegetarian diet or a control group (CG, n=37) following a conventional diet. Both diets were calorie restricted (-500 kcal day(-1)). Participants were examined at baseline, 12 weeks of diet intervention and 24 weeks (subsequent 12 weeks of diet were combined with aerobic exercise). The fatty acid composition of serum phospholipids was measured by gas liquid chromatography. MCR was measured by hyperinsulinemic isoglycemic clamp. Visceral fat (VF) was measured by magnetic resonance imaging. RESULTS: Linoleic acid (LA; 18:2n6) increased in VG (P=0.04), whereas it decreased in CG (P=0.04) in response to dietary interventions. It did not change significantly after the addition of exercise in either group (group × time P<0.001). In VG, changes in 18:2n6 correlated positively with changes in MCR (r=+0.22; P=0.04) and negatively with changes in VF (r=-0.43; P=0.01). After adjustment for changes in body mass index, the association between 18:2n6 and MCR was no longer significant. The addition of exercise resulted in greater changes of phospholipid fatty acids composition in VG than in CG. CONCLUSION: We demonstrated that the insulin-sensitizing effect of a vegetarian diet might be related to the increased proportion of LA in serum phospholipids.
- Publikační typ
- časopisecké články MeSH
