Glucagon-like peptide-1 (GLP-1) is an incretin known for proliferative and antiapoptotic effects on various tissues. Exenatide and Liraglutide are GLP-1 analogues used in clinical practice as antidiabetic drugs. Since GLP-1 and its analogues exert significant effect on liver metabolism and since changes in intermediary metabolism play an important role in the process of liver regeneration, we decided to determine the effect of Exenatide and Liraglutide on the early phase of liver regeneration and selected metabolic parameters in a model of 2/3 partial hepatectomy (PHx) in rats. Animals were submitted either to PHx or laparotomy and received 3 doses of either GLP-1 analogues (Exenatide – 42 μg/kg b.w., Liraglutide – 0.75 mg/kg b.w.) or saline intraperitoneally. We analyzed body and liver weight, liver bromodeoxyuridine incorporation, liver content of DNA, triacylglycerols and cholesterol and biochemical serum parameters. Bromodeoxyuridine labeling was significantly lower in hepatectomized rats receiving either type of GLP-1 analogues when compared to hepatectomized controls. This effect was more pronounced in the Liraglutide group compared to Exenatide (p<0.001). In addition, liver DNA content was lower in
hepatectomized rats receiving Liraglutide than in hepatectomized control rats (p<0.001). In conclusion, GLP-1 analogues Exenatide and Liraglutide significantly inhibited an early phase of liver
regeneration after PHx in rats. This inhibitory effect was more pronounced in rats receiving Liraglutide.
Fatty liver disease associated with obesity is an important medical problem and the mechanisms for lipid accumulation in hepatocytes are not fully elucidated yet. Recent findings indicate that mitochondria play an importan t role in this process. Our data on hepatocytes in which mitochondria are in contact with other cytosolic structures importan t for their function, extend observations obtained on isolated mitochondria and confirm inhibition of Complex I activity in hepatocytes isolated from rats fed by high fat diet (HFD) compared with controls fed by standard diet (STD). Furthermore we have found that HFD- hepatocytes are more sensitive to the peroxidative stress because under these conditions also Complex II activity is disturbed. Therefore in HFD animals decrease of Complex I activity cannot be compensated by Complex II substrates as in STD hepatocytes. Our data thus indicates that combination of HFD and peroxidative stress potentiates HFD damaging effect of mitochondria because both branches of the respiratory chain (NADH- and flavoprotein-dependent) are disturbed., T. Garnol ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The protective effect of S-adenosylmethionine (SAMe) on D-galactosamine (GalN)-induced damage to rat hepatocytes was tested in primary cultures. SAMe at concentrations of 50 and 1000 mg/l significantly reduced lactate dehydrogenase release from cells injured by 40 mM GalN after 24 h of incubation. There were no significant changes in urea production after 24 h among tested groups, including control hepatocytes. Exposure of hepatocytes to GalN leads to 3.5-fold decrease in urea synthesis after 48 h in comparison with control cell cultures. Addition of the highest dose of SAMe (1000 mg/l) into the culture media attenuated this decrease by 180 %. None of the tested doses of SAMe (5, 25, 50 and 1000 mg/l) affected considerably the reduced activity of mitochondrial dehydrogenases. The content of reduced and oxidized glutathione in GalN-exposed cells was diminished to 1.5 % and 16 %, respectively, of the control values after 24 h. Using only the highest concentration SAMe increased significantly these contents. SAMe had no effect on dramatically decreased albumin synthesis. These findings indicate beneficial effect of SAMe, especially of the highest concentration, on GalN-induced toxicity to rat hepatocytes in primary culture. This action of SAMe seems to be associated with reduction of plasma membrane damage and increased synthesis of glutathione.
Sensitivity of various mitochondrial enzymes to oxidative damage was tested on isolated rat liver hepatocytes
permeabilized by digitonin. In permeabilized hepatocytes
normal respiratory control
values were obtained and
mitochondrial membranes remained intact. Respiratory rate
s of NADH-dependent (glutamate+malate, palmitylcarnitine
+ malate) and flavoprotein-dependent (succinate) substrates were determined in hepatocytes exposed for 5 min to
0.5-3 mM
tert
-butyl hydroperoxide before addition of digitonin.
Our data showed that oxidation of NADH-dependent
substrates is much more sensitive to oxidative stress than ox
idation of flavoprotein-dependent ones, evidently due to the
modification of iron-sulfur clusters or SH groups in the NADH dehydrogenase enzyme complex (Complex I).