Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty liver represents the liver component of metabolic syndrome and may be involved in plasminogen activator inhibitor-1 (PAI-1) synthesis. We studied plasma PAI-1 levels and relationships with risk factors for metabolic syndrome, including fatty liver, in 170 patients. Liver ultrasound scan was performed on all patients, and a liver biopsy was performed on those patients with chronically elevated transaminase levels. Plasma PAI-1 levels correlated significantly (P < .05) with body mass index, degree of steatosis, insulin resistance, insulin level, waist circumference, triglycerides, and high-density lipoprotein (HDL) -cholesterol. However, only body mass index (beta = .455) and HDL-cholesterol (beta = .293) remained predictors of PAI-1 levels. Liver biopsy revealed a significant correlation (P < .05) between insulin resistance (r = 0.381) or insulin level (r = 0.519) and liver fibrosis. In patients presenting features of metabolic syndrome, plasma PAI-1 levels were mainly conditioned by the whole-body fat content.
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PMID:Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome. 1816 Jun

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. This cancer develops mainly in cirrhotic patients. The cirrhotic liver is considered to be a preneoplastic organ, suggesting the rationale for cancer prevention. PPARgamma is a nuclear transcription factor whose activation leads to interaction in the metabolism of lipids, insulin sensitization of peripheral cells, anti-inflammatory action. It can also induce differentiation and inhibits proliferation of cancer cells. Until now, data using PPARgamma ligands in HCC have demonstrated mainly in in vitro models that its activation could be due to an antiproliferative effect. PPARgamma ligand administration has also been associated with a diminution of liver fibrosis in animal models, and potentially also on tumoral cell death. Soma data show that the favorable effect of natural and synthetized PPARgamma agonists could also be independent of PPARgamma activation. Furthermore, in some situations, PPARgamma antagonists have also an anticancer effect. Therefore, we can conclude that the link between activation of the PPARgamma pathway and an anticancer activity is suggested but until now not firmly established in HCC.
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PMID:The Role of PPARgamma in Hepatocellular Carcinoma. 1850 97

The TGFbeta1/Smad pathway plays a critical role in cholestasis and liver fibrosis. Previous studies show that TGFbeta1, TNFalpha, and insulin inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription and bile acid synthesis in human hepatocytes. In this study, we investigated insulin, TGFbeta1, and TNFalpha regulation of rat Cyp7a1 gene transcription. In contrast to inhibition of human CYP7A1 gene transcription, TGFbeta1 stimulates rat Cyp7a1 reporter activity. Smad3, FoxO1, and HNF4alpha synergistically stimulated rat Cyp7a1 gene transcription. Mutations of the Smad3, FoxO1, or HNF4alpha binding site attenuated the rat Cyp7a1 promoter activity. Furthermore, TNFalpha and cJun attenuated TGFbeta1 stimulation of rat Cyp7a1. Insulin or adenovirus-mediated expression of constitutively active AKT1 inhibited FoxO1 and Smad3 synergy. In streptozotocin-induced diabetic rats, Cyp7a1 mRNA expression levels were induced and insulin attenuated CYP7A1 mRNA levels. Chromatin immunoprecipitation assay showed that FoxO1 binding to Cyp7a1 chromatin was increased in diabetic rat livers and insulin reduced FoxO1 binding. These results suggest a mechanistic basis for induction of Cyp7a1 activity and bile acid synthesis in cholestatic rats and in diabetic rats. The crosstalk of insulin, TGFbeta and TNFalpha signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes, fatty liver disease, and liver fibrosis.
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PMID:TGFbeta1, TNFalpha, and insulin signaling crosstalk in regulation of the rat cholesterol 7alpha-hydroxylase gene expression. 1851 45

Hepcidin inhibits intestinal absorption of iron through internalisation of ferroportin. Its discovery helps to better understand the genetic iron overloads. The insulin resistance-hepatic iron overload (IR-HIO)--also coined as the dysmetabolic iron overload syndrome--is a common cause or iron overload. This article is a review about genetic iron overloads and IR-HIO. Type 1 haemochromatosis C282Y +/+ accounts for 95% of the haemochromatosis. Hepatic fibrosis may develop if serum ferritin is higher than 1000 microg/l but can be partially reversible with phlebotomies. Juvenile haemochromatosis (type 2) and type 3 haemochromatosis (mutation of the transferrin receptor 2) are very uncommon. Several mutations of the ferroportin gene can cause usually mild iron overload of autosomal dominant inheritance. Aceruleoplasminemia is an uncommon disorder involving cerebral iron overload. The causes and consequences of the IR-HIO are unknown. Treatment of IR-HIO is focused on metabolic syndrome and phlebotomies are questionable because the overload is moderate and intestinal absorption of iron seems to be low. MRI (or other non invasive methods) is needed to truly assess iron overload because serum ferritin overestimates it in metabolic syndrome. Several points have to be elucidated: how HFE interferes with hepcidin in type 1 haemochromatosis; the causes of variability of iron overload; the benefits of populations screening; the advantage of phlebotomies in IR-HIO; the use of new oral iron chelators.
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PMID:[Genetic iron overloads and hepatic insulin-resistance iron overload syndrome: an update]. 1858 23

Liver fibrosis is a dynamic process consisting of the chronic activation of the wound healing reaction in response to reiterated liver damage, leading to the excessive deposition of fibrillar extracellular matrix into the liver and eventually, if the cause of injury is not removed, to liver cirrhosis. The term "adipokines" identifies a group of polypeptide molecules secreted primarily by adipose tissue, which exert local, peripheral and/or central actions. Additionally to their well-established role in controlling adipose tissue physiology, adipokines have been shown to be involved in different obesity-related diseases, such as hypertension, atherosclerosis and type 2 diabetes. Accumulating data demonstrate that obesity and insulin resistance are associated with a more severe and faster progression of the fibrogenic process in different chronic liver diseases. Therefore, numerous recent studies have analyzed the role played by adipokines in the hepatic wound healing process, identifying novel roles as modulators of liver pathophysiology. This review summarizes the more significant and recent findings concerning the role played by adipocyte-derived molecules, such as leptin, adiponectin and resistin, in the liver fibrogenic process. The actions of different adipokines on the biology of liver resident cells, as well as their effects in different animal models of liver injury are discussed. The variations in the circulating levels and in the intrahepatic expression of these molecules occurring in patients with different chronic liver diseases will be also analyzed.
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PMID:The role of adipokines in liver fibrosis. 1860 1

Non-alcoholic steatohepatitis (NASH) is a part of the spectrum of non-alcoholic fatty liver disease (NAFLD), which can progress to hepatic cirrhosis and end-stage liver disease or hepatocellular carcinoma (HCC). Its pathogenesis is associated with insulin resistance (IR) and the metabolic syndrome. Hepatic steatosis has also been considered an early marker of IR. It is now accepted that NASH is a multistep process with a prominent role for IR, where oxidative stress and cytokines retain a central role. Markers for predicting NAFLD with advanced fibrosis are needed. Once considered irreversible, liver fibrosis is now recognized a dynamic process with significant prospects for remission. The liver biopsy is still a gold standard in assessment of liver fibro-inflammatory activity in the injured liver, but has its own limitations: invasiveness, small tissue sample and inter- and intra-observer error. The lack of non-invasive tests limits the ability of monitoring progression of hepatic fibrosis and response to treatment. Therefore, clinical trials focused on finding of new non-invasive diagnostic tools giving possibilities of frequent, more accurate and reproducible assessment of hepatic fibrosis are constantly conducted.
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PMID:[Non invasive markers of non-alcoholic steatohepatitis]. 1894 40

Nonalcoholic fatty liver disease (NAFLD) is a condition pathogenically linked to metabolic syndrome (MS) by insulin resistance (IR), and characterized by hepatic steatosis in the absence of significant alcohol use, hepatotoxicity, and/or other known liver diseases.The principles of NAFLD therapy target IR: the key point of MS. As the renin-angiotensin system (RAS) plays a central role in IR, and subsequently in NAFLD and nonalcoholic steatohepatitis (NASH), an attempt to block the deleterious effects of RAS overexpression seems a logical target. While many potential therapies tested in NASH target only the consequences of this condition, or try to "get rid" of excessive fat, angiotensin receptor blockers (ARBs) could act as an elegant tool for adequate correction of the various imbalances that act in harmony in NASH/NAFLD. Indeed, by inhibiting RAS we can improve the intracellular insulin signaling pathway, better control adipose tissue proliferation and adipokine production, and produce more balanced local and systemic levels of various cytokines. At the same time, by controlling the local RAS in the liver we might be able to prevent at least fibrosis and also slow down the vicious cycle that links steatosis to necroinflammation. By targeting the pancreatic effects of angiotensin we should be able to preserve an adequate insulin secretion and acquire a better metabolic balance.In our opinion there are two major advantages of ARBs that make them a possible therapeutic option for treating NASH and MS: their specific antihypertensive effect, and their impact on liver fibrosis. In light of this, and based on the current evidence (including existent human studies), we can speculate that some ARBs like telmisartan, candesartan, and losartan can be beneficial in treating NASH/NAFLD and its consequences, and further larger controlled clinical trials will bring consistent data into this field.
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PMID:Angiotensin receptor blockers in the treatment of NASH/NAFLD: could they be a first-class option? 1897 77

Our mechanistic understanding of liver fibrosis has increased dramatically in recent years for all liver diseases and for hepatitis C and nonalcoholic steatohepatitis (NASH) in particular. Hepatitis C causes liver injury and fibrosis through direct cytopathic means, direct and indirect interactions with hepatic stellate cells, and activation of the immune system. Steatosis and insulin resistance, which are intrinsic deficits in NASH, are also of great importance in hepatitis C and may be induced by viral or host metabolic factors. For NASH, the key mediators of damage include oxidative stress, fat compartmentalization, visceral fat, apoptosis, and adipokine derangement. This article explores in depth the disease-specific mechanisms of fibrosis in hepatitis C and NASH, with a focus on recent developments.
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PMID:Disease-specific mechanisms of fibrosis: hepatitis C virus and nonalcoholic steatohepatitis. 1898 68

Recent studies have revealed a close relationship between insulin resistance (IR) and the progression of chronic liver diseases, although relatively little is known regarding the possible mechanisms involved. The aim of this study was to elucidate the impact of IR on the development of liver fibrosis and hepatocarcinogenesis using obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Liver fibrosis development and glutathione-S-transferase placental form (GST-P)-positive pre-neoplastic lesions were both markedly accelerated in OLETF rats, being induced by pig serum and diethylnitrosamine (DEN), respectively. In the fibrosis experiment, alpha-smooth muscle actin-positive activated hepatic stellate cells (HSCs) also significantly increased in OLETF rats along with augmentation of the hepatic collagen content and transforming growth factor-beta1. Our in vitro study showed that both glucose and insulin stimulated the proliferation of activated HSCs, and the combination treatment exerted an additive effect. In the DEN model, neovascularization, which plays a pivotal role in hepatocarcinogenesis, was up-regulated in OLETF rats almost in parallel with pre-neoplastic lesion development and a potent angiogenic factor, vascular endothelial growth factor. High glucose and insulin also significantly augmented the in vitro neovascularization via extracellular signal-regulated kinase 1/2 phosphorylation. Similar to the effect on the activated HSCs, co-existence of both factors exerted a more potent effect than either single factor. In conclusion, these results indicated that the IR status directly accelerated liver fibrosis development and hepatocarcinogenesis at least partly through the stimulation of activated HSC proliferation and hepatic neovascularization, respectively, in the rat.
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PMID:Impact of insulin resistance on the progression of chronic liver diseases. 1902 Jul 79

Meckel syndrome (MKS) is a ciliopathy characterized by encephalocele, cystic renal disease, liver fibrosis and polydactyly. An identifying feature of MKS1, one of six MKS-associated proteins, is the presence of a B9 domain of unknown function. Using phylogenetic analyses, we show that this domain occurs exclusively within a family of three proteins distributed widely in ciliated organisms. Consistent with a ciliary role, all Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia. Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins. This localization is evolutionarily conserved, because the human orthologues also localize to basal bodies, as well as cilia. As reported for MKS1, disrupting human MKSR1 or MKSR2 causes ciliogenesis defects. By contrast, single, double and triple C. elegans mks/mksr mutants do not display overt defects in ciliary structure, intraflagellar transport or chemosensation. However, we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling. Our findings therefore demonstrate functional interactions between a novel family of proteins associated with basal bodies or cilia, providing new insights into the molecular etiology of a pleiotropic human disorder.
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PMID:Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. 1920 69


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