In the isolated rat liver perfused in situ stimulation of the nerve bundles around the portal vein and the hepatic artery caused an increase of urate formation that was inhibited by the α1-blocker prazosine and the xanthine oxidase inhibitor allopurinol. Moreover, nerve stimulation increased glucose and lactate output and decreased perfusion flow. Infusion of noradrenaline had similar effects. Compared to nerve stimulation infusion of glucagon led to a less pronounced increase of urate formation and a twice as large increase in glucose output but a decrease in lactate release without affecting the flow rate. Insulin had no effect on any of the parameters studied.

Intravenous feeding of patients with essential and balanced nutrition is required when enteral feeding is not tolerated, therefore indicating the need for Total Parenteral Nutrition (TPN). This life-saving therapy is also associated with the increase risk of intrahepatic cholestasis. The incidence of TPN-related hepatobiliary complications is common in both adults and infants on TPN. Previous work in in vivo models suggested that one of the potential contributing factors is the aluminum contamination of TPN solutions. The mechanism by which aluminum contributes to the PNAC development, though, was unknown. Aluminum as a risk factor may influence a number of hepatocellular functions to lead to cholestasis but one possible mechanism is the potential for aluminum to cause dysfunction of those transporters responsible in the maintenance of bile flow. To provide some initial information regarding the role of aluminum as a contributing factor to cholestasis and the possible underlying mechanism, cytotoxicity studies were conducted to determine whether aluminum causes direct toxicity of HepG2 cells. Furthermore, the influence of aluminum on the mRNA expression of hepatic biliary transporters (BSEP, MRP2, MATE1, NTCP) and nuclear transcription factor (FXR) in HepG2 cells using real-time RT-PCR analysis was assessed. Since inflammation is a component of cholestasis, these investigations also involved the use of an inflammatory stimulus, lipopolysaccharide (LPS), to determine whether the effects of aluminum were exacerbated by underlying inflammation. My data suggest that for the canalicular hepatic transporters MATE1 and BSEP, aluminum at higher concentration alone as well as with LPS caused increased mRNA expression levels. In addition to this, BSEP mRNA expression was preserved and that of MATE1 was increased on LPS exposure. Given the particular importance of BSEP in the maintenance of bile flow and reported effects of drug-induced inhibition of BSEP to cause hepatic cholestasis, the influence of aluminum on BSEP (and MATE1) protein expression and activity warrant investigation. Further studies may identify that inhibition of BSEP function (and possibly MATE1) by aluminum contamination of total parenteral nutrition formulations may explain, in part, the intrahepatic cholestasis associated with parenteral nutrition.

Apoptosis is a genetically regulated form of cell death that occurs when the cell is exposed to physiological, pathogenic, or cytotoxic stimuli. Unregulated apoptosis (too much or too little apoptosis) at any time from embryogenesis to adulthood, can result in a variety of disease states, such as neurodegenerative disorders, autoimmunity, cardiovascular disease, liver and kidney problems, and cancer. A reasonable estimation is that either too little or too much cell death contributes to half of the main medical illnesses for which adequate therapy or prevention is lacking. The apoptotic pathways can be initiated by reactive oxygen species (ROS) and inflammatory molecules, both of which are believed to be up-regulated in a state of obesity. In addition, multiple studies have shown that the risk of developing cardiovascular disease, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and certain types of cancers increase with increasing degree of obesity in both men and women. Despite the well characterized association of obesity and disease incidence, the mechanisms by which obesity contributes to disease pathology are poorly understood. Previously, in our research group, it was shown that obese Zucker rats, which are the animal model of human obesity, are more prone to colon cancer and hepatic steatosis compare to their relative lean counterparts. Therefore, applying Real-Time RT-PCR, the expression levels of some pro- and anti-apoptotic members of the BCL-2 family of genes were investigated to figure out the possible effect of obesity on apoptotic gene expression levels. Also, apoptotic gene expression patterns of obese and lean Zucker rats after DNA damage induction were compared to each other in order to find the possible connection of apoptotic gene expression with disease progression in obese individuals. This is the first study comparing the expression level of BCL-2 family of genes in obese versus lean liver and colon tissue. In this study, it was shown that an obese genotype affects pro- and anti-apoptotic gene expression levels and patterns whether or not DNA damage has been induced in both liver and colon. The results show a clear alteration in apoptotic gene expression levels in obese individuals compared to their lean counterparts leading to the proposal that apoptosis may be involved in the obesity related colon cancer and liver steatosis.

The overall objective of this research was to investigate the status of tumor necrosis factor-α (TNF-α), and molecules associated with its signaling, in the pathological state of hepatic steatosis. The effect of NSAID piroxicam, a cancer preventive agent also known to affect TNF-α signaling on hepatic steatosis, was also investigated. The biological state of the tissue was assessed by examining the expression of TNF-α signaling molecule in whole tissue, as well as in hepatic lipid raft. Lipid rafts are dynamic assemblies of cholesterol and sphingolipids, microdomains that form in the exoplasmic leaflet of the biological membranes shown to play a role in compartmentalization, modulation and integration of the cell signaling. In the present research, Zucker obese rats were used as a model of human obesity and insulin resistant state. These rats exhibit hepatic steatosis in adulthood similar to those noted in obese individuals. Female Zucker obese and lean rats (5 weeks old) were fed a semisynthetic diet with or without piroxicam (150 ppm). Zucker lean counterparts served as control. After 8 weeks of feeding, rats were euthanized and liver from each animal was collected. Liver tissue from each animal was processed for histology and biochemical analysis which included lipids and proteins (COX-1 and 2, TNF-α, TNF-RI and RII, IKK-β, IκB-α and NF-κB). Liver histology and the level of total lipids confirmed that Zucker obese rats had hepatic steatosis, which was further augmented by piroxicam treatment. Whole tissue protein expression, using western blot, showed that the steatotic liver differed from non-steatotic livers by having lower levels of TNF-RII. TNF-RII showed a trend which was inversely proportional to the pathological state of the tissue. The obese-piroxicam liver had the lowest level of TNF-RII and lean livers had the highest (p<0.05). The total NF-κB level was higher in the obese and obese-piroxicam groups compared to the lean or lean-piroxicam groups (p<0.05). Piroxicam treatment lowered the level of NF-κB in obese and lean livers. IκB-α was higher in obese livers than in lean livers. The nuclear level of NF-κB by western blot analysis showed the same pattern as noted in the whole tissue homogenate. However, the difference in the level between obese and lean was marked. The obese nuclei contained two to three fold higher levels of NF-κB protein than the lean liver nuclei. IκB-α level was significantly higher in the obese liver tissues and nuclei than their lean counterparts. While transcriptionally active NF-κB was higher (p<0.05) in the obese livers than in the lean livers, the difference between obese and lean groups was not as significant as that noted for the level of NF-κB assessed by western blot. This suggests that the proportion of active NF-κB present in the nuclear fraction is much higher in the lean than in the obese nuclei. Lipid raft was extracted and identified successfully from obese and lean livers. The total caveolin and flotillin levels were significantly higher in the liver lipid rafts of the obese-piroxicam than that of the other groups. This is the group that also exhibited higher steatosis. Piroxicam treatment significantly decreased the level of caveolin in the lean liver and significantly increased the level of flotillin in the obese liver. While COX-1 was not detectable, however, the level of COX-2 and TNF-RII in lipid raft was opposite to the level noted in the whole tissue homogenate. TNFRII was highest in the obese-piroxicam lipid raft and lowest in the lean-piroxicam lipid raft. TNF-RII, COX-2, IκB-α and NF-κB proteins were the molecules profoundly affected by the pathological state of the tissue and piroxicam treatment. This research is the first to report the presence of IκB-α in the nuclear compartment with a higher level in the nuclei and whole tissue in the obese liver than in the lean liver. This research demonstrates that TNF-α to NF-κB axis is altered in steatotic liver, and analysis of lipid rafts in steatotic and non-steatotic liver demonstrates that lipid rafts play a distinct role in modifying the biological availability of key proteins in the pathological state of liver steatosis.

Apoptosis is a genetically regulated form of cell death that occurs when the cell is exposed to physiological, pathogenic, or cytotoxic stimuli. Unregulated apoptosis (too much or too little apoptosis) at any time from embryogenesis to adulthood, can result in a variety of disease states, such as neurodegenerative disorders, autoimmunity, cardiovascular disease, liver and kidney problems, and cancer. A reasonable estimation is that either too little or too much cell death contributes to half of the main medical illnesses for which adequate therapy or prevention is lacking. The apoptotic pathways can be initiated by reactive oxygen species (ROS) and inflammatory molecules, both of which are believed to be up-regulated in a state of obesity. In addition, multiple studies have shown that the risk of developing cardiovascular disease, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and certain types of cancers increase with increasing degree of obesity in both men and women. Despite the well characterized association of obesity and disease incidence, the mechanisms by which obesity contributes to disease pathology are poorly understood. Previously, in our research group, it was shown that obese Zucker rats, which are the animal model of human obesity, are more prone to colon cancer and hepatic steatosis compare to their relative lean counterparts. Therefore, applying Real-Time RT-PCR, the expression levels of some pro- and anti-apoptotic members of the BCL-2 family of genes were investigated to figure out the possible effect of obesity on apoptotic gene expression levels. Also, apoptotic gene expression patterns of obese and lean Zucker rats after DNA damage induction were compared to each other in order to find the possible connection of apoptotic gene expression with disease progression in obese individuals. This is the first study comparing the expression level of BCL-2 family of genes in obese versus lean liver and colon tissue. In this study, it was shown that an obese genotype affects pro- and anti-apoptotic gene expression levels and patterns whether or not DNA damage has been induced in both liver and colon. The results show a clear alteration in apoptotic gene expression levels in obese individuals compared to their lean counterparts leading to the proposal that apoptosis may be involved in the obesity related colon cancer and liver steatosis.

Tissue slices can be made from organs, such as liver, kidney, brain, and heart, and from various species including humans, dogs, non-human primates, rats and mice. It has been demonstrated that human and rat liver slices are viable for up to 2 days, and liver slices have been extensively used as an in vitro method to study hepatic drug metabolism and toxicity in humans. The objective of this study was to determine the utility of canine hepatic slices as an in vitro model for studying drug metabolism and hepatotoxicity in dogs. Canine hepatic slices were incubated in media containing various drugs to determine the hepatotoxicity of the agents and the ability of the slices to metabolize the drugs. The toxicity of phenobarbital, primidone, lidocaine and carprofen to canine hepatic slices was assessed by determining changes in supernatant concentrations of potassium ions and adenosine triphosphate (ATP); histologic lesions were determined as necrosis, extent of vacuolation and severity of vacuolation. Xenobiotic drug metabolizing enzymatic activity was investigated by determining the metabolism of lidocaine to monoethylglycinexylidide (MEGX), and administration of phenobarbital plus primidone was used as a positive control for hepatotoxicity in dogs. The function of drug-metabolizing enzymes was demonstrated by the successful metabolism of lidocaine to MEGX. Carprofen, a drug which causes idiosyncratic hepatic disease in dogs, did not show any hepatotoxicity at concentrations of 10, 50 and 100 µg/ml using potassium ion levels, ATP concentrations and histology as indicators of hepatotoxicity. Slices incubated in media without drug showed no toxicity over 24 hours based on potassium ion and ATP supernatant concentrations while significant increases in histologic lesions were noted at 8, 12 and 24 hours. Canine hepatic slices were a useful model for examining drug metabolism and toxicity for up to 24 hours.

BACKGROUND: Diaclyglycerol (DAG) oil has the potential as an effective weight control agent as well as an agent to modify overweight related complications. OBJECTIVE: We aim to examine the efficacy of DAG oil (Enova oilTM) on regulating energy expenditure (EE), fat oxidation, body composition, lipid profiles and hepatic lipogenesis in comparison with conventional oils. DESIGN: Twenty-six overweight hypertriglyceridemic women consumed DAG or control oil for 28 days separated by a 4-week washout period using a randomized crossover design. Forty grams of either DAG or control oil were consumed daily by each study subject. RESULTS: DAG oil consumption for a period of 4-week does not alter total EE, fat oxidation, lean mass, fasting lipid profile or fatty acids synthesis rate, but effectively reduces (p<0.05) body weight and adiposity. CONCLUSION: DAG oil maybe an useful agent in the battle against obesity. However, its body weight/composition control effects are not from increasing of lean mass, or postprandial EE and fat oxidation. The consumption of DAG oil for a period of 4-week does not necessarily modify fasting lipid profiles or hepatic lipogenesis to reduce risk of coronary heart diseases in overweight hypertriglyceridemic subjects.

BACKGROUND: Diaclyglycerol (DAG) oil has the potential as an effective weight control agent as well as an agent to modify overweight related complications. OBJECTIVE: We aim to examine the efficacy of DAG oil (Enova oilTM) on regulating energy expenditure (EE), fat oxidation, body composition, lipid profiles and hepatic lipogenesis in comparison with conventional oils. DESIGN: Twenty-six overweight hypertriglyceridemic women consumed DAG or control oil for 28 days separated by a 4-week washout period using a randomized crossover design. Forty grams of either DAG or control oil were consumed daily by each study subject. RESULTS: DAG oil consumption for a period of 4-week does not alter total EE, fat oxidation, lean mass, fasting lipid profile or fatty acids synthesis rate, but effectively reduces (p<0.05) body weight and adiposity. CONCLUSION: DAG oil maybe an useful agent in the battle against obesity. However, its body weight/composition control effects are not from increasing of lean mass, or postprandial EE and fat oxidation. The consumption of DAG oil for a period of 4-week does not necessarily modify fasting lipid profiles or hepatic lipogenesis to reduce risk of coronary heart diseases in overweight hypertriglyceridemic subjects.

Hemodinamikos pokyčiai kepenų operacijų metu yra svarbūs perioperacinėms išeitims. Tyrimo tikslas: išsiaiškinus hemodinaminių pokyčių pobūdį bei priežastis parinkti optimalią pacientų monitoravimo metodiką darant kepenų rezekci¬nes operacijas. Tikslui pasiekti iškelti šie uždaviniai: palyginti širdies minutinio tūrio monitoravimo neinvaziniu impe¬dan¬so kardiografijos būdu vertę su invaziniu intermituojančios termodiliucijos būdu pacientams, kuriems daromos kepenų rezek¬cijos, nustatyti dažniausiai kintančius hemodinaminius parametrus kepe¬nų operacijų metu, nustatyti hemodinaminių rodiklių pokyčių priežastis, rasti hemodinaminius veiksnius, įtakojančius didesnį kraujo nete¬kimą operacijos metu. Remiantis tyrimo rezultatais, daromos šios išvados: siekiant sumažinti perioperacinį sergamumą ir mirštamumą darant kepenų rezekcijas būtina monitoruoti centrinės hemodinamikos ro¬dik¬lius. Širdies minutinio tūrio monitoravimui tinka saugus, nebrangus ir tikslus neinvazinis impedanso kardiografijos metodas. Kepenų rezekcinių operacijų metu stebimi hemodinaminiai pokyčiai yra vidurinio arterinio kraujo spaudimo sumažėjimas (hipotenzija), susijęs su širdies indekso su¬ma¬žėjimu, ir slėgio apatinėje tuščiojoje venoje padidėjimas. Hipotenzijos bei širdies indekso sumažėjimo priežastis dažniau yra apatinės tuščiosios venos perspaudimas, pasireiškiantis didėjančiu slėgiu šlaunies venoje, kurį sąlygoja chirurginės manipuliacijos. Hipotenzijos priežastį kepenų rezekcinių operacijų metu galima... [toliau žr. visą tekstą] / Aim of the study: select optimal methods for patient’s monitoring du¬ring hepatic resection after evaluation the character, causes and rate of hemodynamic changes. Main goals: to compare the value of non-invasive impedance cardiography for moni¬toring of cardiac output to invasive intermittent thermodilution method in patients undergoing hepatic resection, to determine mostly changing hemodynamic parameters during the hepatic surgery, to determine the causes of hemodynamic changes, to determine hemodynamic factors, influencing increase in blood loss during the surgery. Conclusions: non-invasive ICG method may be used to monitor cardiac output during the hepatic resection surgery, most common hemodynamic changes during hepatic resection surgery include the reduction in mean arterial blood pressure (hypotension), decreased cardiac index, and elevated pressure in the inferior vena cava, more common cause of hypotension is clamping of the inferior vena cava, which is caused by surgical manipulations; less common – blood loss. Cause of hypotension during hepatic resection surgery may be determined by pressure monitoring in the superior and inferior vena cava, blood loss is related to the number of clamping of the inferior vena cava and increasing pressure in the superior vena cava. Practical recommendations: in order to reduce the number of hemodynamic changes during the surgery, it is essential to monitor arterial blood pressure, cardiac output and pressures in the superior and... [to full text]

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