Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.

• MeSH
• cholestáza chemicky indukované   metabolismus   patologie   MeSH
• ethinylestradiol škodlivé účinky   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• homeostáza účinky léků   MeSH
• intestinální absorpce účinky léků   MeSH
• metformin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Excessive iron accumulation in the liver, which accompanies certain genetic or metabolic diseases, impairs bile acids (BA) synthesis, but the influence of iron on the complex process of BA homeostasis is unknown. Thus, we evaluated the effect of iron overload (IO) on BA turnover in rats. Compared with control rats, IO (8 intraperitoneal doses of 100 mg/kg every other day) significantly decreased bile flow as a consequence of decreased biliary BA secretion. This decrease was associated with reduced expression of Cyp7a1, the rate limiting enzyme in the conversion of cholesterol to BA, and decreased expression of Bsep, the transporter responsible for BA efflux into bile. However, IO did not change net BA content in faeces in response to increased intestinal conversion of BA into hyodeoxycholic acid. In addition, IO increased plasma cholesterol concentrations, which corresponded with reduced Cyp7a1 expression and increased expression of Hmgcr, the rate-limiting enzyme in de novo cholesterol synthesis. In summary, this study describes the mechanisms impairing synthesis, biliary secretion and intestinal processing of BA during IO. Altered elimination pathways for BA and cholesterol may interfere with the pathophysiology of liver damage accompanying liver diseases with excessive iron deposition.

• MeSH
• biologické markery MeSH
• cholesterol metabolismus   MeSH
• exprese genu MeSH
• játra metabolismus   patologie   MeSH
• krysa rodu rattus MeSH
• messenger RNA genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• oxidační stres MeSH
• přetížení železem etiologie   metabolismus   patologie   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mesenchymal stem cells have the ability to differentiate into insulin-producing cells, raising the hope for diabetes mellitus treatment. The aim of this research was to study the ability of stem cells from discarded natal teeth to differentiate into insulinproducing cells. Two vital human natal teeth were obtained from a healthy 2-day-old female. Stem cells from the dental pulp were isolated, cultured under xenogenic-free conditions, propagated and characterized. Proliferative activity, population doubling time and viability were measured, and the multipotent differentiation ability was investigated. A twostep protocol was used to induce the human natal dental pulp stem cells to differentiate into insulinproducing cells. Phenotypic analysis was done using flow cytometry. Immunohistochemistry was performed to detect insulin and C-peptide. PDX1, HES1 and Glut2 gene expression analysis was performed by quantitative reverse transcription-polymerase chain reaction. Human natal dental pulp stem cells were able to undergo osteogenic, chondrogenic and adipogenic differentiation upon exposure to the specific differentiation media for each lineage. Their differentiation into insulin-producing cells was confirmed by expression of C-peptide and insulin, as well as by 975.4 % higher expression of PDX-1 and 469.5 % higher expression of HES1 in comparison to the cells cultivated in standard cultivation media. Glut2 transporter mRNA was absent in the non-differentiated cells, and differentiation of the stem cells into insulin-producing cells induced appearance of the mRNA of this transporter. We were the first to demonstrate that stem cells obtained from the pulp of natal teeth could be differentiated into insulinproducing cells, which might prove useful in the stem cell therapy for type 1 diabetes.

• MeSH
• beta-buňky cytologie   metabolismus   MeSH
• buněčná diferenciace fyziologie   MeSH
• C-peptid metabolismus   MeSH
• diabetes mellitus 1. typu metabolismus   MeSH
• homeodoménové proteiny metabolismus   MeSH
• imunohistochemie MeSH
• inzulin metabolismus   MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   MeSH
• průtoková cytometrie MeSH
• trans-aktivátory metabolismus   MeSH
• transkripční faktor HES1 metabolismus   MeSH
• zubní dřeň cytologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH