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)

Hepatic steatosis is associated with significant morbidity and mortality after liver resection and transplantation. Although apoptosis is a key mechanism of reperfusion injury in the normal liver, the pathway leading to cell death in steatotic hepatocytes is unknown. A model of hepatic ischemia and reperfusion injury in fatty and lean Zucker rats was used. Fatty animals had increased aspartate aminotransferase (AST) release and decreased survival after 60 minutes of ischemia compared with lean animals. Apoptosis was the predominant form of cell death in the lean rats (82%), whereas necrosis was minimal. In contrast, fatty animals developed only moderate amounts of apoptosis but showed massive necrosis (73%) after 24 hours of reperfusion. Intracellular mediators of apoptosis, such as caspase 8, caspase 3, and cytochrome c, were significantly lower in the steatotic than in the lean liver indicating dysfunction in activation of the apoptotic pathway. The high percentage of necrosis in the steatotic rats was associated with renal acute tubular necrosis after 24 hours of reperfusion in the fatty, but not in lean rats. Caspase inhibition significantly decreased reperfusion injury in lean animals, but was ineffective in fatty animals. The results indicate that the increased susceptibility of fatty livers to reperfusion injury is associated with a change from an apoptotic form of cell death to necrosis. We conclude that new therapeutic strategies are necessary in the fatty liver.
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PMID:Mechanisms of ischemic injury are different in the steatotic and normal rat liver. 1109 35

Fatty livers are sensitive to lipopolysaccharide (LPS) damage. This study tests the hypothesis that this vulnerability occurs because protective, antiapoptotic mechanisms are not upregulated appropriately. Genetically obese, leptin-deficient ob/ob mice, a model for nonalcoholic fatty liver disease, and their lean litter mates were treated with a small dose of LPS. General measures of liver injury, early (i.e., cytochrome c release) and late (i.e., activation of caspase 3) events that occur during hepatocyte apoptosis, and various aspects of the signal transduction pathways that induce nuclear factor-kappaB (NF-kappaB) and several of its antiapoptotic transcriptional targets (e.g., inducible nitric oxide synthase, bfl-1, and bcl-xL) were compared. Within 0.5-6 h after LPS exposure, cytochrome c begins to accumulate in the cytosol of normal livers, and procaspase 3 cleavage increases. Coincident with these events, kinases (e.g., AKT and Erk-1 and -2) that result in the degradation of inhibitor kappa-B are activated; NF-kappaB activity is induced, and NF-kappaB-regulated gene products accumulate. Throughout this period, there is negligible histological evidence of liver damage, and serum alanine aminotransferase values barely increase over baseline values. Although ob/ob livers have significant histological liver injury and 11-fold greater serum alanine aminotransferase values than those of lean mice by 6 h post-LPS, they exhibit greater activation of AKT and Erk, more profound reductions in inhibitor kappa-B, enhanced activation of NF-kappaB, and greater induction of NF-kappaB-regulated genes. Consistent with this heightened antiapoptotic response, increases in cytochrome c and procaspase 3 cleavage products are inhibited. Together with evidence that ob/ob hepatocytes have a reduced ATP content and undergo increased lysis after in vitro exposure to tumor necrosis factor-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather than because of apoptosis.
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PMID:Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation. 1144 19

Steatosis is increasingly recognized as a cofactor influencing the progression of fibrosis in chronic hepatitis C; however, the mechanisms by which it contributes to liver injury remain uncertain. We studied 125 patients with chronic hepatitis C to assess the effect of steatosis on liver cell apoptosis and the expression of Bcl-2, Bcl-x(L), Bax, and tumor necrosis factor alpha (TNF-alpha) and the relationship between liver cell apoptosis and disease severity. A significant increase in liver cell apoptosis was seen in liver sections with increasing grade of steatosis (r = 0.42; P <.0001). Hepatic steatosis and previous heavy alcohol consumption were the only two variables independently associated with the apoptotic index. Increasing steatosis was associated with decreased Bcl-2 mRNA levels and an increase in the proapoptotic Bax/Bcl-2 ratio (r = -0.32, P =.007; and r = 0.27, P =.02, respectively). In the absence of steatosis, increased liver cell apoptosis was not associated with stellate cell activation or fibrosis (r = 0.26, P =.11; r = 0.06, P =.71, respectively). In contrast, in the presence of steatosis, increasing apoptosis was associated with activation of stellate cells and increased stage of fibrosis (r = 0.35, P =.047; r = 0.33, P =.03, respectively), supporting the premise that the steatotic liver is more vulnerable to liver injury. In patients with hepatitis C virus genotype 3, there was a significant correlation between TNF-alpha mRNA levels and active caspase-3 (r = 0.54, P =.007). In conclusion, these observations suggest a mechanism whereby steatosis contributes to the progression of liver injury in chronic hepatitis C. Further investigation will be required to determine the molecular pathways responsible for the proapoptotic effect of steatosis and whether this increase in apoptosis contributes directly to fibrogenesis.
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PMID:Steatosis and liver cell apoptosis in chronic hepatitis C: a mechanism for increased liver injury. 1512 51

Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.
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PMID:Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis. 1523 17

In traditional oriental medicine, Yin-Chen-Hao decoction is used for the remedy of liver diseases such as hepatitis, fatty liver, hepatocirrhosis and jaundice. However, despite extensive pharmacological study, the molecular mechanism of the anti-inflammatory effect of Yin-Chen-Hao decoction is poorly understood. In this study, we have investigated the pharmacological action on the mechanism of concanavalin A-induced T cell-dependent hepatitis in mice. Concanavalin A administration resulted in a severe liver injury. This was shown through increased levels of serum transaminase and lactic dehydrogenase, and increased liver DNA fragmentation and caspase-3 activity. Pretreatment with the aqueous extract from Yin-Chen-Hao decoction dose-dependently inhibited the elevation in transaminase and lactic dehydrogenase activity, and reduced liver DNA fragmentation and caspase-3 levels. There was an improvement in histological changes including inflammatory infiltration, hepatocyte necrosis and degeneration, and Kupffer cell hyperplasia. In addition, Yin-Chen-Hao decoction significantly inhibited tumour necrosis factor-alpha (TNF-alpha) production in-vitro and in-vivo. Moreover, the activation of nuclear factor kappa B (NF-kappaB), which regulates TNF-alpha production, was blocked by Yin-Chen-Hao decoction in-vitro and in-vivo. In conclusion, Yin-Chen-Hao decoction was capable of regulating T-cell-mediated liver injury in-vivo. This event may have depended on the decrease of TNF-alpha production through the inhibition of NF-kappaB activation.
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PMID:Aqueous extract of Yin-Chen-Hao decoction, a traditional Chinese prescription, exerts protective effects on concanavalin A-induced hepatitis in mice through inhibition of NF-kappaB. 1664 Aug 37

In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3-generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median [interquartile range]: 765.7 U/L [479.6-991.1], 202.4 U/L [160.4-258.2], 215.5 U/L [150.2-296.2], respectively; P < .001). Cytokeratin-18 fragment levels independently predicted NASH (OR 1.95; 95% CI 1.18-3.22; P = .009 for every 50 U/L increase). A cutoff value of 395 U/L calculated using the receiver operating characteristic curve approach showed a specificity of 99.9%, a sensitivity of 85.7%, and positive and negative predictive values of 99.9% and 85.7%, respectively, for the diagnosis of NASH. In conclusion, these findings strongly suggest that determination of hepatocyte caspase activation in the blood is a strong and independent predictor of NASH in human subjects. These data highlight the potential usefulness of this test as a noninvasive diagnostic means of determining histological disease severity in patients with NAFLD.
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PMID:In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. 1725 23

Total parenteral nutrition (TPN) induces a high rate of liver disease in infants, yet the pathogenesis remains elusive. We used neonatal piglets as an animal model to assess early events leading to TPN-mediated liver injury. Newborn piglets (n = 7) were nourished for 7 d on TPN or enteral nutrition (EN) and the liver tissue and isolated hepatocytes were subjected to morphologic and molecular analysis. Histological analysis revealed prominent steatosis (grade > 2) in 6 of 7 TPN pigs, whereas minimal steatosis (grade < or = 1) was observed in only 2 EN pigs. Abundant cytosolic cytochrome C and DNA fragmentation were observed in hepatocytes from TPN compared with EN piglets. Markers of mitochondrial and Fas-mediated apoptosis were altered in TPN liver tissue, as indicated by a lower ATP concentration (P < 0.05), accumulation of ubiquitin, 9.9-fold activation of caspase-3 activity (P < 0.01), and increased cleavage of poly-(ADP-ribose) polymerase, caspase-8, -9, and -7 when compared with EN livers. Bcl-2 and proliferating cell nuclear antigen expression was downregulated, whereas Fas and Bax were upregulated in TPN livers. However, levels of caspase-12 and Bip/GRP78, both markers of endoplasmic reticulum-mediated apoptosis, did not differ between the groups. Short-term TPN induces steatosis and oxidative stress, which results in apoptosis mediated by the mitochondrial and Fas pathways. Thus, TPN-induced steatosis in newborn piglets may serve as a novel animal model to assess the pathogenesis of fatty liver and apoptosis-mediated liver injury in infants.
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PMID:Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets. 1698 24

Hepatocyte apoptosis was recently described for NASH patients. The pathomechanisms are incompletely understood, but upregulation of the death receptor Fas was detectable on hepatocytes of NASH patients. We analyzed the sensitivity of fatty liver against CD95/Fas-mediated apoptotic cell death by injection of agonistic anti-Fas antibody (Jo2) in obese ob/ob mice and lean control animals. Ob/ob mice died within 12 hrs, whereas control animals survived. Liver enzymes were significantly increased compared to those in control mice (P < 0.001). Histological analysis and also TUNEL assay of liver sections from ob/ob mice exhibited massive liver injury. Activity of caspase 3 was significantly more enhanced in livers of ob/ob mice after Jo2 challenge. The increased sensitivity was confirmed in vitro by using ob/ob-derived primary hepatocytes. CD95 expression was similar in ob/ob and control mice. However, hepatocytes from ob/ob mice revealed a decreased mitochondrial membrane potential, suggesting that mitochondria play a potential role in this increased susceptibility.
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PMID:Enhanced sensitivity to CD95-induced apoptosis in ob/ob mice. 1741 59

Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR. Oleic acid (500 microM) alone did not induce apoptosis, while palmitic acid (500 microM) increased apoptosis 5-fold. GCDCA did not induce significant apoptosis at low micromolar concentrations (5-30 microM) in non-steatotic cells. However, at the same concentrations, GCDCA increased apoptosis 3-fold in oleic acid-pretreated HepG2-Ntcp cells and 3.5-fold in primary rat hepatocytes. Pretreatment with oleic acid increased GCDCA-induced gene transcription of the proinflammatory cytokines IL-8 and IL-22 5-fold and 19-fold, respectively. Thus, low levels of cholestasis normally not considered harmful could advance liver injury in patients with NAFLD.
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PMID:Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis. 1845 8

Silymarin, used by 30 to 40% of liver disease patients, is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. Previous studies have only described the pharmacokinetics for two flavonolignans, silybin A and silybin B, in healthy volunteers. The aim of this study was to determine the pharmacokinetics of the major silymarin flavonolignans in liver disease patients. Healthy volunteers and three patient cohorts were administered a single, 600-mg p.o. dose of milk thistle extract, and 14 blood samples were obtained over 24 h. Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 to 38% in liver disease cohorts as a result of accumulation of silychristin (20-36%). Area under the curve (AUC(0-24h)) for the sum of total silymarin flavonolignans was 2.4-, 3.3-, and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, nonalcoholic fatty liver disease (p <or= 0.03), and HCV cirrhosis cohorts (p <or= 0.03), respectively, compared with healthy volunteers (AUC(0-24h) = 2021 ng . h/ml). Caspase-3/7 activity correlated with the AUC(0-24h) for the sum of all silymarin conjugates among all subjects (R(2) = 0.52) and was 5-fold higher in the HCV cirrhosis cohort (p <or= 0.005 versus healthy). No correlation was observed with other measures of disease activity, including plasma alanine aminotransferase, interleukin 6, and 8-isoprostane F(2alpha), a measure of oxidative stress. These findings suggest that the pharmacokinetics of silymarin is altered in patients with liver disease. Patients with cirrhosis had the highest plasma caspase-3/7 activity and also achieved the highest exposures for the major silymarin flavonolignans.
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PMID:The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic Fatty liver disease and correlates with plasma caspase-3/7 activity. 1856 43


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