Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-alcoholic steatohepatitis (NASH) may progress to liver cirrhosis, and NASH patients with liver cirrhosis have a risk of development of hepatocellular carcinoma. Peroxisome proliferator-activated receptor (PPAR) gamma ligand has recently been reported to have improved the condition of patients with NASH. The aim of this study was to investigate whether pioglitazone, a PPARgamma ligand, has any influence on the animal model of NASH as well as isolated hepatic stellate cells. In vivo, the effects of pioglitazone were examined using the choline-deficient L-amino acid-defined (CDAA)-diet liver fibrosis model. After two weeks, pioglitazone improved hepatic steatosis, prevented liver fibrosis, and reduced preneoplastic lesions in the liver after 10 weeks. Pioglitazone reduced the expression of TIMP-1 and TIMP-2 mRNA without changing MMP-13 mRNA expression compared to the liver fed a CDAA diet alone. In vitro, pioglitazone prevented the activation of hepatic stellate cells resulting in reducing the expression of type I procollagen, MMP-2, TIMP-1, and TIMP-2 mRNA with increased MMP-13 mRNA expression. These results indicate that pioglitazone may be one of the candidates for the benefit drugs for the liver disease of patients with NASH.
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PMID:Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. 1501 44

Hepatic stellate cells (HSC) undergo transdifferentiation (activation) from lipid-storing pericytes to myofibroblastic cells to participate in liver fibrogenesis. Our recent work demonstrates that depletion of peroxisome proliferator-activated receptor gamma (PPARgamma) constitutes one of the key molecular events for HSC activation and that ectopic expression of this nuclear receptor achieves the phenotypic reversal of activated HSC to the quiescent cells. The present study extends these findings to test a novel hypothesis that adipogenic transcriptional regulation is required for the maintenance of HSC quiescence. Comparative analysis of quiescent and activated HSC in culture reveals higher expression of putative adipogenic transcription factors such as CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBPbeta, C/EBPdelta, PPARgamma, liver X receptor alpha, sterol regulatory element-binding protein 1c and of adipocyte-specific genes in the quiescent cells. Conversely, activated HSC have increased expression of PPARbeta, a transcription factor known to promote fatty acid oxidation. A treatment of activated HSC with the adipocyte differentiation mixture (isobutylmethylxanthine, dexamethasone, and insulin) or ectopic expression of PPARgamma or SREBP-1c in these cells, induces a panel of adipogenic transcription factors, reduces PPARbeta, and causes the phenotypic reversal to quiescent HSC. These results support the importance of adipogenic transcriptional regulation in HSC quiescence and provide a new framework for identifying novel molecular targets for the treatment of liver cirrhosis.
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PMID:Adipogenic transcriptional regulation of hepatic stellate cells. 1553 55

Liver fibrosis is the consequence of chronic or repeated liver injury caused by hepatotoxic agents like alcohol and viruses, as well as immune and congenital metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), caused by obesity and abnormal lipid metabolism, may be the latest known cause of liver fibrosis and cirrhosis. Furthermore, NAFLD with obesity can provide a terrain in which alcoholic and viral liver diseases, such as chronic hepatitis C, are prone to cause liver cirrhosis. Insulin, insulin-like growth factor (IGF)-1, peroxisome proliferator-activated receptors (PPARs), leptin, adiponectin, and preadipocyte factor-1/delta-like1 (Pref-1/dlk1) are hormones, growth factors, nuclear receptors, and cytokines that are actively involved in lipid metabolism. They share common target cells important in liver fibrosis, i.e., hepatic stellate cells (HSCs). Activation of HSCs is known to initiate and perpetuate liver fibrosis. Insulin and IGF-1 stimulate HSC activation and collagen production in vitro. However, IGF-1 alleviates liver fibrosis in vivo. Ligands of PPARy inhibit HSC activation and collagen synthesis in vivo and in vitro, and are helpful in decreasing liver fibrosis. But ligands of PPARbeta enhance proliferation of HSCs. Leptin is profibrogenic, and liver fibrosis is decreased in leptin- or leptin receptor-deficient mice. Adiponectin is, on the contrary, anti-fibrogenic. Extensive liver fibrosis may develop in adiponectin-knockout mice and is alleviated by administration of recombinant adiponectin. Pref-1/dlkl is implicated in fibrogenesis of the liver through its modulation of HSCs. The use of such biologically active molecules in lipid metabolism as ligands of PPARgamma and adiponectin might not help slim down a patient on the whole, but can potentially be used to halt the progression of liver fibrosis. Weight reduction, a strategy for controlling obesity and metabolic syndromes, may also be a tool for decreasing NAFLD and alleviating liver cirrhosis.
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PMID:An adipocentric view of liver fibrosis and cirrhosis. 1575 75

Nonalcoholic steatohepatitis (NASH) is a condition characterized by excessive deposition of fat in the liver (steatosis), inflammation and hepatocellular necrosis. While steatosis alone is generally a benign and stable condition, NASH can have a dire prognosis in a minority of patients, mainly because of fibrosis occurrence and progression to cirrhosis. Life-threatening complications such as liver failure and hepatocellular carcinoma have been described in NASH-induced cirrhosis. Insulin resistance is almost universally found in patients with NASH and the main risk factors for this condition are overweight and diabetes. Improvement in insulin sensitivity, whether achieved by diet, exercise and/or pharmacological interventions, results in a dramatic reduction of liver fat and inflammation and fibrosis as well. Therefore NASH should be viewed as the hepatic phenotypic manifestation of insulin resistance and a bona fide component of the metabolic syndrome. Liver injury should be assessed in diabetic and/or obese patients and the mechanisms by which insulin resistance promotes liver damage needs to be elucidated. The encouraging results of the use of PPARgamma agonists and, in particular, rosiglitazone, in human or experimental models of NASH, justifies future large-scale, randomized controlled trials.
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PMID:[Nonalcoholic steatohepatitis]. 1595 6

We investigated the immunohistochemical distribution of active NF-kappaB p65 and peroxisome proliferator-activated receptor (PPAR) subtypes alpha and gamma in the different phases of liver steatonecrosis and cirrhosis induced in rats after 3 and 9 weeks of carbon tetrachloride (CCl4) intoxication. CCl4 treatment can induce changes in the expression of NF-kappaB and PPARs. Immunohistochemical analysis of liver tissue sections from rats with steatonecrosis or cirrhosis demonstrated a significant increase in the number of NF-kappaB-positive and TNF-alpha-positive hepatocytes and Kupffer cells. In healthy controls, no expression of active NF-kappaB was detected. In previous studies, we have demonstrated that Kupffer cells isolated from rats with CCl4-induced steatonecrosis produced more reactive oxygen intermediates than cells isolated from normal rats. These oxidants could activate NF-kappaB and lead to an overexpression of TNF-alpha, observed in liver tissue sections. After CCl4 ingestion, the rat livers demonstrated a significantly decreased number of hepatocytes expressing PPARalpha and PPARgamma and a significantly increased number of ED2-positive Kupffer cells expressing these transcription factors, compared to normal. The activation of the p65 isoform of NF-kappaB correlates negatively with transcription of the alpha and gamma isoforms of PPAR in hepatocytes, and positively in Kupffer cells. These results suggest that the regulation and the role of these two transcription factors differ in the two cell types studied.
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PMID:Immunohistochemical distribution of activated nuclear factor kappaB and peroxisome proliferator-activated receptors in carbon tetrachloride-induced chronic liver injury in rats. 1595 96

Administration of a choline-deficient, l-amino acid-defined (CDAA) diet to rats causes steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, a pathology similar to that observed in non-alcoholic steatohepatitis (NASH). The aim of this study was to evaluate if a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, pioglitazone (PGZ), could ameliorate CDAA diet-induced fatty liver and cirrhosis. Rats were fed a CDAA diet for 1 week and were given the CDAA diet for an additional week with or without PGZ (2-week model). Also, after administration of the CDAA diet for 12 weeks, rats were administered the CDAA diet for an additional 4 weeks with or without PGZ (16-week model). The CDAA diet, administered for either one or 12 weeks, induced fatty liver or cirrhosis with up-regulation of hepatic PPAR-gamma expression, respectively. In the 2-week model, rats treated with PGZ for 1 week demonstrated significantly lower hepatic triglyceride content and serum levels of tumor necrosis factor-alpha. In the 16-week model, treatment for 4 weeks with PGZ ameliorated hepatic fibrosis with a decrease in the expression of procollagen, alpha-smooth muscle actin, and transforming growth factor-beta1 in comparison to rats without PGZ. These results suggest that PPAR-gamma agonist is a potential therapeutic modality to treat NASH.
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PMID:The peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet. 1608 55

Transdifferentiation of hepatic stellate cells (HSC) constitutes a major cellular event in the genesis of alcoholic liver fibrosis and cirrhosis and molecular mechanisms underlying this process is incompletely understood. Our laboratory proposed several years ago that HSC quiescence requires the transcriptional program known to be integral to preadipocyte to adipocyte differentiation. In support of the hypothesis, our research demonstrates the expression of adipogenic transcription factors (C/EBPs, PPARgamma, SREBP-1c, LXRalpha) and adipocyte-specific genes (adipsin, resistin) are high in quiescent HSC and depleted in activated HSC. Three gain-of-function approaches have been taken to test this notion: the treatment of activated HSC with the adipocyte differentiation cocktail; ectopic expression of PPARgamma or SREBP-1c. All three treatments coordinately upregulate a panel of putative adipogenic transcription factors and cause morphologic and biochemical reversal of activated HSC to quiescent cells. These findings establish a new conceptual framework for the treatment of liver fibrosis and propose an intriguing notion concerning the plasticity of HSC.
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PMID:Adipogenic phenotype of hepatic stellate cells. 1634 97

Nonalcoholic fatty liver disease (NAFLD) is a frequent and potentially progressive chronic liver disease that occurs in subjects who do not abuse alcohol. NAFLD is often associated with obesity, metabolic syndrome and insulin resistance and its more aggressive form, nonalcoholic steatohepatitis (NASH) is a major cause of cryptogenic cirrhosis. NAFLD/NASH are commonly detected because of elevated serum aminotransferase levels, ultrasonographic fatty liver and, at liver histology, steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Current management of NAFLD/NASH is largely conservative and includes diet regimen, aerobic exercise, and interventions towards the associated metabolic abnormalities. The main concern is therefore to decrease liver steatosis and its progression toward steatohepatitis and fibrosis, and the risk of "cryptogenic" cirrhosis. Among the most promising medications, weight reducing drugs, insulin sensitizers and lipid-lowering agents, antioxidants, bile salts, co-factors increasing the mitochondrial transport of fatty acids are being considered. Among them, thiazolidinediones are the most promising drug family that act by activating PPARgamma nuclear receptors and by regulating both microsomal and peroxisomal lipid oxidative pathways. Pharmacological treatment of obesity and probiotics should be considered as potential therapeutic options. In this review, after summarizing the general background on fatty liver, the most current and attractive pharmacological approaches to the problem of NAFLD/NASH are discussed.
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PMID:Current pharmacological treatment of nonalcoholic fatty liver. 1707 35

Primary lipodystrophies represent a heterogeneous group of very rare diseases with a prevalence of less than 1 case for 100.000, inherited or acquired, caracterized by a loss of body fat either generalized or localized (lipoatrophy). In some forms, lipoatrophy is associated with a selective hypertrophy of other fat depots. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes and hypertriglyceridemia leading to a risk of acute pancreatitis. Chronic complications are those resulting from diabetes involving the retina, kidney and nerves, cardiovascular complications and steatotic liver lesions that could result in cirrhosis. Genetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyl-transferase involved in triglyceride synthesis. Acquired generalized lipodystrophy (Lawrence syndrome) is of unknown origin but is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C belonging to the nuclear lamina, or in PPARG encoding the adipogenic transcription factor PPARgamma. Some less typical lipodystrophies, associated with signs of premature aging, have been linked to mutations in LMNA or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome) is characterized by cephalothoracic fat loss. Its aetiology is unknown but mutations in LMNB2, encoding the lamina protein lamin B2, could represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes. The genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis could be proposed. Treatment of diabetes, dyslipidemia and complications involves the classical intervention strategies. Insulino-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels reported good results with respect to the metabolic and liver alterations. The prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.
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PMID:[Primary lipodystrophies]. 1732 32

Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg/day per body for 24 weeks), a synthetic ligand for PPARgamma, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPARgamma pathway in NASH and the therapeutic utility of a PPARgamma ligand.
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PMID:Life style-related diseases of the digestive system: gene expression in nonalcoholic steatohepatitis patients and treatment strategies. 1792 38


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