INTRODUCTION: The aim of study was to evaluate impact of long-term dietary cholesterol overload on the cholesterol homeostasis and liver regeneration. MATERIAL AND METHODS: Serum lipid parameters, 14C-cholesterol incorporation, liver DNA synthesis and protein expression was determined in partially hepatectomized (PH) rats fed with a standard (SLD) or hypercholesterolemic (CHOL) diet. RESULTS: 29-day intake of CHOL diet before PH produced increase in serum total cholesterol, LDL lipoprotein, and triglyceride concentration. PH provoked decrease in serum total cholesterol and triglyceride concentration in both groups. PH was associated with increase in serum ALT activity more pronounced in CHOL animals. Hepatic DNA synthesis was increased after PH in both groups, but lower in CHOL. Hypercholesterolemic diet reduced the absorption of radiolabelled cholesterol in intestine and then activity in blood and liver. The 14C-cholesterol hepatic activities tend to increase after PH in both groups. CHOL diet produced up-regulation of Acyl-CoA:cholesterol acyltransferase-2 protein expression. PH was associated with increase of LDL receptor and Acyl-CoA:cholesterol acyltransferase-2 protein expression in both dietary groups. DISCUSSION: Liver regeneration after PH is negatively influenced by CHOL diet. The increased uptake of cholesterol in the liver after PH associated with up-regulation of LDL receptor protein expression suggests preferential use of extrahepatic cholesterol by the liver.
- MeSH
- cholesterol dietní farmakologie MeSH
- cholesterolacyltransferasa účinky léků metabolismus MeSH
- DNA účinky léků metabolismus MeSH
- hepatektomie MeSH
- játra účinky léků metabolismus patologie MeSH
- krysa rodu rattus MeSH
- lipoproteiny LDL účinky léků metabolismus MeSH
- potkani Wistar MeSH
- radioizotopy uhlíku MeSH
- regenerace jater účinky léků MeSH
- triglyceridy metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. Since HMB is synthesized in the liver, unique effects of exogenous HMB intake may be hypothesized in subjects with liver disease, in which muscle wasting is frequently found. We studied effects of HMB on the liver and soleus (SOL) and extensor digitorum longus (EDL) muscles in partially-hepatectomized (PH) rats. HMB or saline was infused using osmotic pumps to PH or sham-operated rats for 7 days. We found lower body weight and protein content in EDL of PH rats treated with saline than in sham-operated animals. These effects were insignificant in HMB treated animals. In blood plasma of PH rats treated with HMB we found lower concentrations of creatinine and higher concentrations of urea and branched-chain amino acids (BCAA; valine, leucine, and isoleucine) than in PH animals treated with saline. HMB increased BCAA concentrations in SOL and EDL of PH animals and decreased proteolysis in EDL of both sham-operated and PH animals. In the livers of PH rats treated with HMB we found higher DNA content, DNA fragmentation, and BCAA concentrations than in saline-treated animals. The results indicate that HMB affects metabolism of BCAA and has positive influence on protein balance in muscles. Further studies are needed to clarify the effect of HMB on liver regeneration.
- MeSH
- fragmentace DNA účinky léků MeSH
- hepatektomie škodlivé účinky trendy MeSH
- infuzní pumpy MeSH
- játra účinky léků metabolismus MeSH
- kosterní svaly účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- regenerace jater účinky léků fyziologie MeSH
- tělesná hmotnost účinky léků fyziologie MeSH
- valeráty aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- experimenty na zvířatech MeSH
- hepatocyty cytologie imunologie účinky léků MeSH
- interleukin-6 aplikace a dávkování farmakologie MeSH
- multipotentní kmenové buňky transplantace MeSH
- nádory jater chirurgie MeSH
- prasata MeSH
- proliferace buněk fyziologie účinky léků MeSH
- regenerace jater * imunologie účinky léků MeSH
- terapeutická embolizace metody MeSH
- TNF-alfa aplikace a dávkování farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- alkoholická cirhóza jater diagnóza prevence a kontrola terapie MeSH
- biliární cirhóza diagnóza etiologie terapie MeSH
- chronická nemoc MeSH
- ezofageální a žaludeční varixy etiologie prevence a kontrola terapie MeSH
- hepatitida C terapie MeSH
- hepatitida etiologie klasifikace komplikace MeSH
- jaterní cirhóza * diagnóza etiologie terapie MeSH
- jaterní hvězdicovité buňky cytologie patologie MeSH
- lidé MeSH
- myofibroblasty fyziologie patologie účinky léků MeSH
- nemoci jater * etiologie klasifikace terapie MeSH
- portální hypertenze etiologie prevence a kontrola terapie MeSH
- prognóza MeSH
- regenerace jater * fyziologie imunologie účinky léků MeSH
- ztučnělá játra diagnóza etiologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
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 microg/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.
- MeSH
- glukagonu podobný peptid 1 analogy a deriváty MeSH
- hepatektomie trendy MeSH
- krysa rodu rattus MeSH
- liraglutid farmakologie MeSH
- peptidy farmakologie MeSH
- potkani Wistar MeSH
- regenerace jater účinky léků fyziologie MeSH
- živočišné jedy farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Phenylbutyrate is recommended in urea cycle disorders and liver injury to enhance nitrogen disposal by the urine. However, hypothetically there may be adverse responses to the use of phenylbutyrate in the treatment of liver disease because of its role as a histone deacetylase inhibitor and its stimulatory effect on branched-chain alpha-keto acid dehydrogenase, the rate-limiting enzyme in the catabolism of branched-chain amino acids (BCAA; valine, leucine and isoleucine). We report the effects of phenylbutyrate on liver regeneration and amino acid levels in plasma of partially hepatectomized (PH) rats. Phenylbutyrate or saline was administered at 12-h intervals to PH or laparotomized rats. Phenylbutyrate delayed the onset of liver regeneration compared to the saline-treated controls, as indicated by lower hepatic DNA specific activities 18 and 24( ) h post-PH, decreased hepatic fractional protein synthesis rates 24 h post-PH and lowered the increases in liver weights and hepatic protein and DNA contents 48 h after PH. Hepatic DNA fragmentation (a hallmark of apoptosis) was higher in the phenylbutyrate-treated animals than in controls. Phenylbutyrate decreased the glutamine and BCAA concentrations and the ratio of the BCAA to aromatic amino acids (phenylalanine and tyrosine) in the blood plasma in both hepatectomized and laparotomized animals. In conclusion, the delayed onset of liver regeneration and the decrease in BCAA/AAA ratio in blood suggest that phenylbutyrate administration may be disastrous in subjects with acute hepatic injury and BCAA supplementation is needed when phenylbutyrate is used therapeutically.
- MeSH
- aminokyseliny metabolismus MeSH
- amoniak metabolismus MeSH
- fenylbutyráty škodlivé účinky MeSH
- glutamin metabolismus MeSH
- hepatektomie metody MeSH
- játra účinky léků metabolismus MeSH
- potkani Wistar MeSH
- regenerace jater účinky léků MeSH
- větvené aminokyseliny účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- Silybin,
- MeSH
- hepatitida zvířat farmakoterapie MeSH
- inzerce jako téma MeSH
- kočky MeSH
- ostropestřec mariánský * MeSH
- pankreatitida farmakoterapie veterinární MeSH
- psi MeSH
- regenerace jater * účinky léků MeSH
- rostlinné extrakty farmakologie terapeutické užití MeSH
- S-adenosylmethionin * farmakologie terapeutické užití MeSH
- semena rostlinná MeSH
- silymarin farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- kočky MeSH
- psi MeSH
- zvířata MeSH
BACKGROUND: Steatohepatitis is a type of histopathological liver injury that can be caused by chemotherapy [chemotherapy-associated steatohepatitis (CASH)] and can progress to liver fibrosis or cirrhosis. CASH impairs liver functions, including liver regeneration. Impaired liver regeneration reduces the number of patients who can undergo liver resection and reduces opportunities for curative therapies. Transforming growth factor-beta (TGFβ) is a potent mitotic inhibitor that participates during the last phase of liver regeneration. TGFβ has been studied as a potential solution to the development of liver fibrosis or hepatocellular carcinoma. AIM: The first aim of our study was to establish a large animal model of toxic liver injury and test the ability of a monoclonal antibody against TGFβ (MAB-TGFβ) to increase liver-regeneration capacity. The second aim was to evaluate the degree to which early preoperative administration of MAB-TGFβ influenced hepatic parenchyma regeneration following healthy liver resection in a swine experimental model. MATERIALS AND METHODS: Toxic liver injury was induced by alcohol consumption and regular intraperitoneal administration of carbon tetrachloride (CCl4) to piglets for 10 weeks. After 10 weeks, the piglets underwent liver resection of the left lateral and left medial liver lobes. Twenty-four hours after liver resection, MAB-TGFβ was administered to the experimental group (10 piglets) and a physiological solution to the control group (10 piglets) through an implemented port-a-cath. In the second part of the study, either MAB-TGFβ or a saline solution control were administered at 12 and 4 days prior to resection of the right lobes of healthy liver (six experimental and 10 control group subjects). Observation and follow-up was performed throughout the entire experiment. Ultrasound and biochemical tests (for albumin, cholinesterase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin, urea, creatinine and ammonia levels) were performed on postoperative days 1, 3, 7, 10 and 14. A histopathological examination was performed after sacrificing the animals on the 14th postoperative day. RESULTS: No significant differences were observed between groups when using ultrasound volumetry to assess the regenerative volume of the liver in both experiments. The only significant differences found when comparing biochemical parameters between groups were higher serum levels of both creatinine and γ-glutamyl transferase in the experimental group with preoperative administration of MAB-TGFβ. There were no differences in the histological analyses of hepatic lobule cross-sectional area nor in the proliferative index between animals receiving MAB-TGFβ and those treated with physiological saline solution before resection. Hepatocytic cross-sectional areas were larger in animals treated with physiological solution versus those treated with MAB-TGFβ on the operative day; however, these values were comparable between groups by 14 days following resection. CONCLUSION: We established a large animal model of toxic liver injury that is comparable with CASH. The toxic injury that was induced without pause between administrations was probably more extensive than occurs in CASH, and there was no effect of MAB-TGFβ administration on liver regeneration. MAB-TGFβ administration did not lead to any observable side-effects, indicating that it could be a promising solution for use as an oncologic-targeted treatment.
- MeSH
- chlorid uhličitý MeSH
- ethanol MeSH
- hepatektomie MeSH
- hepatocyty fyziologie MeSH
- játra patologie patofyziologie MeSH
- lékové postižení jater farmakoterapie patofyziologie MeSH
- monoklonální protilátky farmakologie MeSH
- regenerace jater účinky léků MeSH
- Sus scrofa MeSH
- transformující růstový faktor beta1 antagonisté a inhibitory imunologie MeSH
- velikost buňky MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Two-thirds partial hepatectomy (PHx) is an established model for the study of liver regeneration after resection. This process is accompanied by oxidative stress. AIMS: In our study, we tested the effect of epigallocatechin gallate (EGCG), a green tea antioxidant, on the early phase of liver regeneration after PHx. METHODS: Male Wistar rats were divided into five groups: (I) laparotomy + water for intraperitoneal injections, (II) laparotomy + EGCG 50 mg/kg body weight, (III) PHx + water for injections, (IV) PHx + EGCG 20 mg/kg and (V) PHx + EGCG 50 mg/kg, for 3 consecutive days. The rats were killed 24 h after surgery. Biochemical analysis of rat sera was performed. Histological samples were stained with hematoxylin & eosin and bromodeoxyuridine (BrdU). In hepatectomized rats, we also measured plasma malondialdehyde, tissue malondialdehyde, glutathione and cytokines levels, the activity of caspases 3/7, expression of Nqo-1 and HO-1 genes at the mRNA level, and expression of p21, p-p27 and p-p53 genes at the protein level. RESULTS: We observed lower accumulation of BrdU in group V when compared to groups III and IV. The activity of caspases 3/7 and expression of p-p53 were lower in group V than in groups III and IV. Tissue levels of IL-6 were lower in group V when compared to group III. Significant differences were not noted in other parameters. CONCLUSIONS: Administration of EGCG did not stimulate early phase liver regeneration in rats after PHx. There was even lower DNA synthesis in the group treated with a high dose of EGCG.
- MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- cytokiny genetika metabolismus MeSH
- hemoxygenasa-1 genetika metabolismus MeSH
- hepatektomie metody MeSH
- kaspasy genetika metabolismus MeSH
- katechin analogy a deriváty farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- messenger RNA genetika metabolismus MeSH
- NAD(P)H dehydrogenasa (chinon) genetika metabolismus MeSH
- oxidační stres fyziologie MeSH
- potkani Wistar MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- regenerace jater účinky léků MeSH
- regulace genové exprese účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND/AIMS: TGF-β1 is a pleiotropic cytokine that is over expressed in terminal phase of liver regeneration. METHODOLOGY: Twenty-four hours after partial portal vein ligation monoclonal antibody against TGF-β1 (TGF-β1 group, 7 piglets) or physiological solution (control group, 9 piglets) were applied into the central venous catheter. The biochemical parameters (bilirubin, urea, creatinine, alkaline phosphatase, gamma- glutamyl transferase, cholinesterase, aspartate aminotransferase, alanine aminotransferase and albumin) were assessed. The compensatory hypertrophy of the non-occluded liver lobes was evaluated by periodic ultrasonography during the next fourteen days and by histological examination. RESULTS: The acceleration of growth of the hypertrophic liver lobes was maximal between 3rd and 7th postoperative days in comparison with the control group (p<0.05). No important differences in the biochemical or studied histological parameters were proved. CONCLUSIONS: The present study describes a new usage of monoclonal antibody against TGF-β1 in large animal experimental model of partial portal vein ligation.
- MeSH
- biologické markery metabolismus MeSH
- časové faktory MeSH
- hypertrofie MeSH
- játra krevní zásobení účinky léků metabolismus patologie MeSH
- ligace MeSH
- modely u zvířat MeSH
- monoklonální protilátky farmakologie MeSH
- novorozená zvířata MeSH
- prasata MeSH
- proliferace buněk účinky léků MeSH
- regenerace jater účinky léků MeSH
- transformující růstový faktor beta1 antagonisté a inhibitory metabolismus MeSH
- vena portae chirurgie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
