Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0015695 (fatty liver)
13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alcohol liver disease (ALD) as well as nonalcoholic fatty liver disease (NAFLD) are two of the most common forms of chronic liver disease worldwide and may progress to cirrhosis and end stage liver disease. ALD and NAFLD seem to share many pathophysiologic mechanisms with the accumulation of lipids in the liver being the first step in the development of both conditions. While mitochondrial dysfunction and production of reactive oxygen species seem to play an important role in the progression from simple steatosis to steatohepatitis in both diseases, the pathogenesis of ALD and NAFLD as it relates to tissue injury remains poorly understood. Insights into these mechanisms are of significant clinical importance because current therapies for both conditions are limited and future therapies will be predicated by an understanding of their pathogenesis. In this review we focused on the current evidence for a central role of hepatocellular apoptosis, a specific form of cell death, in the pathogenesis of ALD and NAFLD as well as the current knowledge regarding the subcellular and molecular mechanisms involve in triggering hepatocyte apoptosis in these diseases.
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PMID:Apoptosis in alcoholic and nonalcoholic steatohepatitis. 1597 May 63

Steatotic livers are highly susceptible to I/R (ischaemia/reperfusion) injury and, therefore, the aim of the present study was to evaluate the in vivo effect of NAC (N-acetylcysteine) on hepatic function in the early and initial late phase of warm liver I/R injury in steatotic rabbits. Twelve New Zealand White rabbits were fed a high-cholesterol (2%) diet. The control group (n=6) underwent lobar liver ischaemia for 1 h, followed by 6 h of reperfusion. In the treated group receiving NAC (n=6), an intravenous infusion of NAC was administered prior to and during the 6 h reperfusion period. Systemic and hepatic haemodynamics were monitored continuously. ALT (alanine aminotransferase) activity and bile production were measured. NMR spectroscopy was used to analyse bile composition. Oxidation of DHR (dihydrorhodamine) to RH (rhodamine) was used as a marker of production of reactive oxygen and nitrogen species. Moderate centrilobular hepatic steatosis was demonstrated by histology. The results showed that NAC administration significantly improved portal flow, hepatic microcirculation, bile composition and bile flow after 5 h of reperfusion. NAC administration was also associated with less hepatocellular injury, as indicated by ALT serum activity, and decreased the oxidation of DHR to RH. In conclusion, NAC administration decreased the extent of I/R injury in the steatotic liver, particularly during the late phase of reperfusion.
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PMID:N-Acetylcysteine ameliorates the late phase of liver ischaemia/reperfusion injury in the rabbit with hepatic steatosis. 1598 89

We studied the roles of hepatitis C virus (HCV) core protein in hepatic steatosis and changes in hepatic lipid metabolism. HCV core protein expression plasmid was transfected in HepG2. Triacylglyceride (TG) and mRNA level associated with lipid metabolism were measured. Male C57BL/6 mice were infected with HCV core recombinant adenovirus and used for lipids and mRNA studies. In HCV core protein-expressing cells, peroxisome proliferator-activated receptor (PPAR)alpha, multidrug resistance protein (MDR) 3, and microsomal triglyceride transfer protein (MTP) were down-regulated 48 hr after transfection. In HCV core protein-expressing mice, hepatic TG content and hepatic thiobarbituric acid-reactive substances increased. PPARalpha, MDR2, acyl-CoA oxidase (AOX), and carnitine palmitoyl transferase-1 (CPT-1) were down-regulated. HCV core protein down-regulated lipid metabolism-associated gene expression, Mdr2, CPT, and AOX, accompanied by down-regulation of PPARalpha. There findings may contribute to the understanding of HCV-related steatosis, induction of reactive oxygen species, and carcinogenesis.
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PMID:Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. 1604 88

Liver fatty acid binding protein (L-FABP) contains amino acids that are known to possess antioxidant function. In this study, we tested the hypothesis that L-FABP may serve as an effective endogenous cytoprotectant against oxidative stress. Chang liver cells were selected as the experimental model because of their undetectable L-FABP mRNA level. Full-length L-FABP cDNA was subcloned into the mammalian expression vector pcDNA3.1 (pcDNA-FABP). Chang cells were stably transfected with pc-DNA-FABP or vector (pcDNA3.1) alone. Oxidative stress was induced by incubating cells with 400 micromol/L H2O2 or by subjecting cells to hypoxia/reoxygenation. Total cellular reactive oxygen species (ROS) was determined using the fluorescent probe DCF. Cellular damage induced by hypoxia/reoxygenation was assayed by lactate dehydrogenase (LDH) release. Expression of L-FABP was documented by regular reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and Western blot. The pcDNA-FABP-transfected cells expressed full-length L-FABP mRNA, which was absent from vector-transfected control cells. Western blot showed expression of 14-kd L-FABP protein in pcDNA-FABP-transfected cells, but not in vector-transfected cells. Transfected cells showed decreased DCF fluorescence intensity under oxidative stress (H2O2 and hypoxia/reoxygenation) conditions versus control in inverse proportion to the level of L-FABP expression. Lower LDH release was observed in the higher L-FABP-expressed cells in hypoxia/reoxygenation experiments. In conclusion, we successfully transfected and cloned a Chang liver cell line that expressed the L-FABP gene. The L-FABP-expressing cell line had a reduced intracellular ROS level versus control. This finding implies that L-FABP has a significant role in oxidative stress.
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PMID:Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells. 1617 9

Hepatic steatosis occasionally progresses to nonalcoholic steatohepatitis. This study was designed to examine whether non-obese patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) were prone to develop hepatic steatosis and whether repeated hypoxemia contributed to the progression of steatohepatitis. This study included 83 OSAHS patients and 41 age-, body mass index (BMI)- and gender-matched non-OSAHS patients diagnosed by polysomnography. Hepatic steatosis was defined by a liver/spleen ratio <0.9 on abdominal computerized tomography, and latent steatohepatitis was evaluated based on serum levels of type III procollagen (P-III-P). Visceral fat (V-fat) accumulated much more in OSAHS patients. Liver/spleen ratios in OSAHS patients correlated negatively with BMI and, especially, with the amount of visceral fat. Serum levels of P-III-P in OSAHS patients correlated negatively with the average of oxygen saturation during sleep, and positively with BMI, the apnea-hypopnea index (AHI) and the amount of V-fat. Multiple regression analysis showed that average SaO(2) was the only explanatory variable for P-III-P values, but AHI, BMI and V-fat was not. These observations confirmed that non-obese patients with OSAHS are at a risk for visceral obesity, and suggested that oxygen desaturation during sleep is a risk for developing latent steatohepatitis, especially in patients with substantial hepatic steatosis.
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PMID:Effects of obstructive sleep apnea syndrome on hepatic steatosis and nonalcoholic steatohepatitis. 1621 91

Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome. The metabolic syndrome is characterized by insulin resistance, which is produced by a complex interaction between genetic factors, macronutrient intake and lifestyle that alters the cytokine profile, cell biology and biochemical milieu of the liver, adipose tissue and striated muscle. The resultant disequilibrium in lipid homeostasis causes triglycerides to accumulate in the liver. An increase in oxidative stress, due to the generation of reactive oxygen species as a result of mitochondrial abnormalities and induction of the cytochrome P-450 system could be one mechanism by which the nonalcoholic fatty liver develops into nonalcoholic steatohepatitis. The pathogenesis of cytologic ballooning and Mallory body formation and their role in NAFLD remain to be defined. In addition, inflammation and fibrosis are likely to be secondary to hepatocyte injury and death.
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PMID:Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease. 1626

Calorie-enriched diet and lack of exercise are causing a worldwide surge of obesity, insulin resistance and lipid accretion in liver (i.e. hepatic steatosis), which can lead to steatohepatitis. Steatosis and nonalcoholic steatohepatitis (NASH) can also be induced by drugs such as amiodarone, tamoxifen and some antiretroviral drugs, including stavudine and zidovudine. There is accumulating evidence that mitochondrial dysfunction (more particularly respiratory chain deficiency) plays a key role in the physiopathology of NASH whatever its initial cause. In contrast, the mitochondrial beta-oxidation of fatty acids can be either increased (as in insulin resistance-associated NASH) or decreased (as in drug-induced NASH). However, in both circumstances, generation of reactive oxygen species (ROS) by the damaged respiratory chain can be augmented. ROS generation in an environment enriched in lipids in turn induces lipid peroxidation which releases highly reactive aldehydic derivatives (e.g. malondialdehyde) that have diverse detrimental effects on hepatocytes and other hepatic cells. In hepatocytes, ROS, reactive nitrogen species and lipid peroxidation products further impair the respiratory chain, either directly or indirectly through oxidative damage to the mitochondrial genome. This consequently leads to the generation of more ROS and a vicious cycle occurs. Mitochondrial dysfunction can also lead to apoptosis or necrosis depending on the energy status of the cell. ROS and lipid peroxidation products also increase the generation of several cytokines (TNF-alpha, TGF-beta, Fas ligand) playing a key role in cell death, inflammation and fibrosis. Recent investigations have shown that some genetic polymorphisms can significantly increase the risk of steatohepatitis and that several drugs can prevent or even reverse NASH. Interestingly, most of these drugs could exert their beneficial effects by improving directly or indirectly mitochondrial function in liver. Finding a drug, which could fully prevent oxidative stress and mitochondrial dysfunction in NASH is a major challenge for the next decade.
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PMID:Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. 1640 28

When specimens of the newt Triturus carnifex, under anaesthesia by submersion in a 0.2% chlorbutol solution for 25 min, are isolated in a respiratory chamber at 18 degrees C containing water with only 1.3 ppm of oxygen, they consume the oxygen completely in about 3 hr, but they can stay alive for many more hours and wake up with no apparent exterior consequences. Hypoxia induces rapid onset of hepatic steatosis and melanosis, as well as a controlled haemolytic process involving a pool of red blood cells of the same order of size as that held as a reserve in the spleen by animals in an aerial habitat. At the origin of the phenomena is an intense response by the hypophysis, histologically detectable 1 hr from the onset of treatment and confirmed 2 hr later by a highly significant increase in the plasma thyroidstimulating hormone (TSH) concentration compared with the controls (41.5 +/- 13.7 microU/L vs. 15.5 +/- 6.2; P < 0.005). The thyroid follicles react by reabsorbing their colloid, but instead of an increase in the plasma free T3 and T4 concentrations, fT3 falls significantly (1.5 +/- 0.3 pg/mL vs., the 2.4 +/- 0.7; P < 0.05), whereas fT4 remains stationary (4.0 +/- 0.5 pg/mL vs. 4.6 +/- 0.8; N.S.). After 6 hr, the plasmatic TSH concentration is still higher than in the controls (27.0 +/- 3.0 microU/L vs. 15.5 +/- 6.2; P < 0.05), whereas fT3 and fT4 remain stable (1.5 +/- 0.3 and 4.4 +/- 0.5 pg/mL, respectively). If T3 or T4 labelled with 125I is administered prior to hypoxia, after 6 hr of treatment the radioactivity is found to be limited exclusively to the liver and kidney; the thyroid, gall bladder and gut result negative, and this does not agree with hypotheses of hormone inactivation by deiodination, sulphation or glucuronidation. This apparently peculiar endocrine path has not been observed in previous studies on hypoxia in vertebrates, because the experiments were always designed to analyse plasma hormone levels after at least 24 hr of hypoxia or during chronic treatments, losing the most interesting phases of the endocrine response. The possibility that the hypoxic newt possesses alternative or complementary metabolic pathways to anaerobic glycolysis to sustain steatogenesis and melanogenesis and maintain the same cardiac activity as the controls is briefly discussed.
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PMID:Thyroid and hypoxic stress in the newt Triturus carnifex. 1643 85

Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neil1 knockout (neil1-/-) and heterozygotic (neil1+/-) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from neil1-/- mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.
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PMID:The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. 1644 48

Oxidative stress and hepatic mitochondria play a role in the pathogenesis of nonalcoholic fatty liver disease. The aim of the present study was to evaluate the role of hepatic mitochondrial dysfunction and oxidative stress in the pathogenesis of the disease. Fatty liver was induced in Wistar rats with a choline-deficient diet (CD; N = 7) or a high-fat diet enriched with PUFAs-omega-3 (H; N = 7) for 4 weeks. The control group (N = 7) was fed a standard diet. Liver mitochondrial oxidation and phosphorylation were measured polarographically and oxidative stress was estimated on the basis of malondialdehyde and glutathione concentrations. Moderate macrovacuolar liver steatosis was observed in the CD group and mild liver steatosis was observed in the periportal area in the H group. There was an increase in the oxygen consumption rate by liver mitochondria in respiratory state 4 (S4) and a decrease in respiratory control rate (RCR) in the CD group (S4: 32.70 +/- 3.35; RCR: 2.55 +/- 0.15 ng atoms of O2 min-1 mg protein-1) when compared to the H and control groups (S4: 23.09 +/- 1.53, 17.04 +/- 2.03, RCR: 3.15 +/- 0.15, 3.68 +/- 0.15 ng atoms of O2 min-1 mg protein-1, respectively), P < 0.05. Hepatic lipoperoxide concentrations were significantly increased and the concentration of reduced glutathione was significantly reduced in the CD group. A choline-deficient diet causes moderate steatosis with disruption of liver mitochondrial function and increased oxidative stress. These data suggest that lipid peroxidation products can impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial reactive oxygen species. These findings are important in the pathogenesis of nonalcoholic fatty liver disease.
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PMID:Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease. 1647 Mar 5


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