Metabolic syndrome (MetS) is a cluster of risk factors that increase the likelihood of developing cardiovascular, metabolic and other diseases. The pharmacological management of MetS often involves polypharmacy, making it essential to understand how drug-metabolising enzymes, transporters, transcription factors and other proteins involved are affected under different metabolic conditions. This study investigated the relative mRNA expression of key hepatic and intestinal genes involved in drug metabolism, including Cyp1a2, Cyp3a23, Cyp2d1, Cyp2c11, Cyp2c6, Cyp2e1, Cyp7a1, Cyp2b1, Cyp2a1, Abcg5, Abcg8, Abcb1, Nr1i3, Nr1i2, Ahr, Gsta1 and Comt, in four nonobese rat models of MetS: hereditary hypertriglyceridaemic (HHTg), spontaneously hypertensive rat (SHR), SHR expressing transgenic human C-reactive protein (SHR-CRP), and bilaterally ovariectomised Wistar (W-OVX), compared to Wistar controls. Gene expression was quantified by RT-PCR with data normalised using the ΔΔCt method. Between the models studied, measurements showed significant differences in the liver. The upregulation of Cyp2c6 and Cyp3a23 was observed only in SHR; upregulated Cyp2d1 was found in SHR as well as in HHTg rats. The downregulated Cyp1a2 was measured in a condition of hypertriglyceridemia, postmenopause or hypertension. These findings highlight model-specific alterations in gene expression that may affect drug metabolism and interactions. The HHTg may be, in particular, a suitable model for preclinical studies focusing on intestinal drug-drug interactions in MetS-related conditions.

• Klíčová slova
• drug metabolism, metabolic syndrome, rat model,
• MeSH
• játra metabolismus   enzymologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• membránové transportní proteiny * genetika   metabolismus   MeSH
• messenger RNA * metabolismus   genetika   MeSH
• metabolický syndrom * genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• receptory cytoplazmatické a nukleární * genetika   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové transportní proteiny * MeSH
• messenger RNA * MeSH
• receptory cytoplazmatické a nukleární * MeSH
• systém (enzymů) cytochromů P-450 * MeSH

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.

• Klíčová slova
• cell senescence, empagliflozin, hereditary hypertriglyceridemic rat model, hypertriglyceridemia, insulin sensitivity, metabolic syndrome,
• MeSH
• aplikace orální MeSH
• benzhydrylové sloučeniny aplikace a dávkování   MeSH
• buňky 3T3-L1 MeSH
• buňky Hep G2 MeSH
• down regulace účinky léků   MeSH
• dyslipidemie farmakoterapie   MeSH
• glifloziny aplikace a dávkování   MeSH
• glukoneogeneze účinky léků   genetika   MeSH
• glukosidy aplikace a dávkování   MeSH
• hmotnostní přírůstek účinky léků   MeSH
• hypertriglyceridemie farmakoterapie   metabolismus   MeSH
• hypoglykemika aplikace a dávkování   MeSH
• inzulinová rezistence MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• lipogeneze účinky léků   genetika   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• oxidační stres účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• tuková tkáň metabolismus   MeSH
• upregulace účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny MeSH
• glukosidy MeSH
• hypoglykemika MeSH