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
There is a great urgency of detecting and monitoring myocardial fibrosis in clinical practice with the aim to improve and personalize therapy against cardiac remodelling. Hence, the aim of this study was to describe alterations in and show potential correlations between the structural characteristics and the molecular and biochemical markers of cardiac remodelling on a model of isoproterenol-induced heart failure. Two groups of 3-month-old male Wistar rats (n = 8 per group) were sacrificed after four weeks of treatment: control (placebo), ISO (5 mg/kg/day intraperitoneally). Chronic ISO treatment led to heart failure (HF) characterized by significant reduction of systolic blood pressure (SBP) accompanied by an increase in left ventricular weight (LVW) along with increased collagen content in the LV. The collagen content correlated negatively with SBP (R = -0.776, P < 0.001) and positively with LVW (R = 0.796, P < 0.001), with Col1a1 (0.83; P < 0.001) and Acta2 (0.73; P < 0.01). Moreover, the mRNA expression of fibrotic remodelling indicator, i.e. TGF-β1 tended to increase, while the level of fibrinolysis markers (MCP-1, TIMP-2, MMP) were unchanged. The plasma markers of collagen, procollagen I C-terminal propeptide (PICP) was 37.34 ± 7.10 pg/mL in control and was reduced by 42% (P < 0.05) in the ISO group and procollagen III N-terminal propeptide (PIIINP) was 1216.7 ± 191.0 pg/mL in control and was decreased by 66% (P < 0.05) in the ISO group. Surprisingly, there was no positive correlation between plasma markers of collagen, i.e. PICP and PIIINP and collagen content or molecular markers of collagen. However, both PICP and PIIINP correlated with BW (R = 0.712, resp. 0.803, P < 0.001), which was significantly reduced (by 25%, P < 0.05) in the ISO group. In conclusion, we assume that the collagen content of the left ventricle does not need unavoidably correlate with plasma markers of collagen, which might be affected by confounding factors in heart failure, such as loss of body weight, presumably associated with a catabolic condition.
- MeSH
- isoprenalin MeSH
- kolagen metabolismus MeSH
- krevní tlak MeSH
- peptidové fragmenty krev MeSH
- potkani Wistar MeSH
- prokolagen krev MeSH
- remodelace komor * MeSH
- srdeční komory metabolismus MeSH
- srdeční selhání chemicky indukované metabolismus patofyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
