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Scaglioni F.,Liver Center | Ciccia S.,Liver Center | Marino M.,Liver Center | Bedogni G.,Liver Research Center | And 2 more authors.
Digestive Diseases | Year: 2011

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have a similar pathogenesis and histopathology but a different etiology and epidemiology. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), without any other evident causes of chronic liver diseases (viral, autoimmune, genetic, etc.), and with an alcohol consumption ≤20-30 g/day. On the contrary, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g/day. The most common phenotypic manifestations of primary NAFLD/NASH are overweight/obesity, visceral adiposity, type 2 diabetes, hypertriglyceridemia and hypertension. The prevalence of NAFLD in the general population in Western countries is estimated to be 25-30%. The prevalence and incidence of NASH and ASH are not known because of the impossibility of performing liver biopsy in the general population. Up to 90% of alcoholics have fatty liver, and 5-15% of these subjects will develop cirrhosis over 20 years. The risk of cirrhosis increases to 30-40% in those who continue to drink alcohol. About 10-35% of alcoholics exhibit changes on liver biopsy consistent with alcoholic hepatitis. Natural histories of NASH and ASH are not completely defined, even if patients with NASH have a reduced life expectancy due to liver-related death and cardiovascular diseases. The best treatment of AFLD/ASH is to stop drinking, and the most effective first-line therapeutic option for NAFLD/NASH is non-pharmacologic lifestyle interventions through a multidisciplinary approach including weight loss, dietary changes, physical exercise, and cognitive-behavior therapy. Copyright © 2011 S. Karger AG, Basel.


Bortolussi G.,International Center for Genetic Engineering and Biotechnology | Zentilin L.,International Center for Genetic Engineering and Biotechnology | Baj G.,University of Trieste | Giraudi P.,Centro Studi Fegato | And 5 more authors.
FASEB Journal | Year: 2012

Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. However, treatment becomes less effective during growth, and liver transplantation is required. To investigate the pathophysiology of the disease and therapeutic approaches in mice, we generated a mouse model by introducing a premature stop codon in the UGT1a1 gene, which results in an inactive enzyme. Homozygous mutant mice developed severe jaundice soon after birth and died within 11 d, showing significant cerebellar alterations. To rescue neonatal lethality, newborns were injected with a single dose of adeno-associated viral vector 9 (AAV9) expressing the human UGT1A1. Gene therapy treatment completely rescued all AAV-treated mutant mice, accompanied by lower plasma bilirubin levels and normal brain histology and motor coordination. Our mouse model of CNI reproduces genetic and phenotypic features of the human disease. We have shown, for the first time, the full recovery of the lethal effects of neonatal hyperbilirubinemia. We believe that, besides gene-addition-based therapies, our mice could represent a very useful model to develop and test novel technologies based on gene correction by homologous recombination. © FASEB.


Lonardo A.,University of Modena and Reggio Emilia | Bellentani S.,Centro Studi Fegato | Ratziu V.,University Pierre and Marie Curie | Loria P.,University of Modena and Reggio Emilia
Expert Review of Gastroenterology and Hepatology | Year: 2011

Studies on pathogenesis tend to blame insulin resistance as the chief pathogenic agent in the development and progression of nonalcoholic steatohepatitis (NASH). In this article, studies reporting histological changes induced by pharmacological therapy and nonpharmacological interventions in NASH are critically reviewed, assuming that analysis of morphological findings can provide further insight into the pathogenesis of NASH. PubMed database analysis provided 16 studies describing light microscopy in adults and three in children; ultrastructural analysis was conducted through electron microscopy in two human and four animal studies. Analysis of the data disclosed methodological issues, such as variable histological criteria, limited series, failure to stratify enrolled patients for their risk of progression and very few electron microscopy studies. Moreover, no particularly convincing 'proof-of-concept' study that might assist in understanding the pathogenesis of NASH was found. It is noteworthy that insulin sensitizers fail to treat NASH in all cases, do not reverse or even worsen mitochondrial abnormalities in NASH and, conversely, histological improvement of disease, at least in some patients, is observed with agents acting through mechanisms other than insulin sensitization, such as vitamin E. The finding that correction of insulin resistance may not be sufficient to successfully treat NASH in the majority of patients seems to conflict with studies on pathogenesis. This might imply that NASH is the shared end result of varying pathogenic mechanisms concurring to determine liver damage to a variable extent in the individual patients. If this hypothesis is true, we should try to tailor treatment to each subject. © 2011 Expert Reviews Ltd.


Chavez-Tapia N.C.,Centro Studi Fegato | Chavez-Tapia N.C.,Medica Sur Clinic and Foundation | Rosso N.,Centro Studi Fegato | Tiribelli C.,Centro Studi Fegato | Tiribelli C.,University of Trieste
Current Medicinal Chemistry | Year: 2011

Non-alcoholic fatty liver disease is regarded as the hepatic manifestation of metabolic syndrome and is an important and common cause of chronic liver disease with a potential to develop end-stage liver disease. While important advances in the pathophysiology have been achieved using genetically modified and diet-induced animal models, in-vitro models have been only recently proposed. These models include primary culture and immortalized cell lines. Here we critically review the characteristics of the in vitro models described, the advantages and limitations of the in vitro approach, and the results derived. © 2011 Bentham Science Publishers Ltd.


Tell G.,University of Udine | Tell G.,Centro Studi Fegato | Vascotto C.,University of Udine | Tiribelli C.,University of Trieste | Tiribelli C.,Centro Studi Fegato
Journal of Hepatology | Year: 2013

The importance of a correct balance between oxidative and reductive events has been shown to have a paramount effect on cell function for quite a long time. However, in spite of this body of rapidly growing evidence, the implication of the alteration of the redox state in human disease has been so far much less appreciated. Liver diseases make no exception. Although not fully comprehensive, this article reports what discussed during an EASL Basic School held in 2012 in Trieste, Italy, where the effect of the alteration of the redox state was addressed in different experimental and human models. This translational approach resulted in further stressing the concept that this topic should be expanded in the future not only to better understand how oxidative stress may be linked to a liver damage but also, perhaps more important, how this may be the target for better, more focused treatments. In parallel, understanding how alteration of the redox balance may be associated with liver damage may help define sensitive and ideally early biomarkers of the disorder. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Giraudi P.J.,Centro Studi Fegato | Bellarosa C.,Centro Studi Fegato | Coda-Zabetta C.D.,Centro Studi Fegato | Peruzzo P.,Centro Studi Fegato | Tiribelli C.,University of Trieste
PLoS ONE | Year: 2011

We have previously reported that exposure of SH-SY5Y neuroblastoma cells to unconjugated bilirubin (UCB) resulted in a marked up-regulation of the mRNA encoding for the Na + -independent cystine:glutamate exchanger System X c - (SLC7A11 and SLC3A2 genes). In this study we demonstrate that SH-SY5Y cells treated with UCB showed a higher cystine uptake due to a significant and specific increase in the activity of System X c -, without the contribution of the others two cystine transporters (X AG - and GGT) reported in neurons. The total intracellular glutathione content was 2 folds higher in the cells exposed to bilirubin as compared to controls, suggesting that the internalized cystine is used for gluthathione synthesis. Interestingly, these cells were significantly less sensitive to an oxidative insult induced by hydrogen peroxide. If System X c - is silenced the protection is lost. In conclusion, these results suggest that bilirubin can modulate the gluthathione levels in neuroblastoma cells through the induction of the System X c -, and this renders the cell less prone to oxidative damage. © 2011 Giraudi et al.


Chavez-Tapia N.C.,Fondazione Italiana Fegato Centro Studi Fegato | Chavez-Tapia N.C.,Centro Studi Fegato | Chavez-Tapia N.C.,Medica Sur Clinic and Foundation | Rosso N.,Fondazione Italiana Fegato Centro Studi Fegato | Tiribelli C.,Fondazione Italiana Fegato Centro Studi Fegato
BMC Gastroenterology | Year: 2012

Background: In vitro exposure of liver cells to high concentrations of free fatty acids (FFA) results in fat overload which promotes inflammatory and fibrogenic response similar to those observed in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). Since the mechanisms of this event have not been fully characterized, we aimed to analyze the fibrogenic stimuli in a new in vitro model of NASH.Methods: HuH7 cells were cultured for 24 h in an enriched medium containing bovine serum albumin and increasing concentrations of palmitic and oleic acid at a molar ratio of 1:2 (palmitic and oleic acid, respectively). Cytotoxic effect, apoptosis, oxidative stress, and production of inflammatory and fibrogenic cytokines were measured.Results: FFA induces a significant increment in the intracellular content of lipid droplets. The gene expression of interleukin-6, interleukin-8 and tumor necrosis factor alpha was significantly increased. The protein level of interleukin-8 was also increased. Intracellular lipid accumulation was associated to a significant up-regulation in the gene expression of transforming growth factor beta 1, alpha 2 macroglobulin, vascular endothelial growth factor A, connective tissue growth factor, insulin-like growth factor 2, thrombospondin 1. Flow cytometry analysis demonstrated a significant increment of early apoptosis and production of reactive oxygen species.Conclusions: The exposure of hepatocytes to fatty acids elicits inflammation, increase of oxidative stress, apoptosis and production of fibrogenic cytokines. These data support a primary role of FFA in the pathogenesis of NAFLD and NASH. © 2012 Chavez-Tapia et al; licensee BioMed Central Ltd.


Bellentani S.,Centro Studi Fegato | Bellentani S.,Centro Studi Fegato Gastroenterologia | Scaglioni F.,Centro Studi Fegato | Marino M.,Centro Studi Fegato | Bedogni G.,Centro Studi Fegato
Digestive Diseases | Year: 2010

Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. The prevalence of NAFLD in the general population of Western countries is 20-30%. About 2-3% of the general population is estimated to have non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocarcinoma. As a rule, the prevalence of NAFLD is higher in males and increases with increasing age, and it is influenced by the diagnostic method and the characteristics of the population, especially lifestyle habits. Population-based studies provide better estimates of the prevalence of NAFLD as compared to autoptic and clinical studies, but few such studies have been performed to date. The diagnosis of NAFLD in population studies is usually obtained by ultrasonography, which is known to underestimate the prevalence of fatty liver. The Dallas Heart Study and the Dionysos Study reported that 30% of the adults in the USA and 25% in Italy have NAFLD. In these studies, 79% and 55% of patients with NAFLD had normal aminotransferase levels, showing that liver enzymes are not surrogate markers of NAFLD in the general population. Noninvasive markers such as the fatty liver index obtained from the Dionysos Study may be useful to screen for NAFLD in the general population. The most important risk factors for NAFLD are male gender, age, obesity, insulin resistance and the cardiometabolic alterations that define the metabolic syndrome. The prevalence of NAFLD is 80-90% in obese adults, 30-50% in patients with diabetes and up to 90% in patients with hyperlipidemia. The prevalence of NAFLD among children is 3-10%, rising up to 40-70% among obese children. Moreover, pediatric NAFLD increased from about 3% a decade ago to 5% today, with a male-to-female ratio of 2:1. The incidence and natural history of NAFLD are still not well defined, but it is recognized that the majority of individuals with NAFLD do not develop NASH. The incidence of NAFLD is probably increasing in Western countries, strictly linked to lifestyle habits. Copyright © 2010 S. Karger AG, Basel.


Gazzin S.,Centro Studi Fegato | Berengeno A.L.,Centro Studi Fegato | Strazielle N.,University of Lyon | Fazzari F.,Centro Studi Fegato | And 5 more authors.
PLoS ONE | Year: 2011

Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16-27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17-P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60-70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4 th ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity. © 2011 Gazzin et al.


Bellentani S.,Centro Studi Fegato
Digestive diseases (Basel, Switzerland) | Year: 2010

Population-based studies on the natural history of chronic viral liver disease that consider co-morbidity factors, such as alcohol or metabolic diseases, are lacking. We report here the contribution of ethanol intake and non-organ-specific autoantibodies (NOSA) to the course of chronic viral disease in the Dionysos cohort. As reported elsewhere, the Dionysos study was performed in two towns of Northern Italy, started in 1992 with 10 years of follow-up in 2002, and allowed us to quantify the burden of chronic liver disease in Northern Italy. We followed 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) years, respectively. The incidence and remission rates of steatosis were 9.0 and 29.7 per 1,000 person-years in the HCV cohort and 4.0 and 30.4 per 1,000 person-years in the HBV cohort. Progression to cirrhosis and hepatocarcinoma was more common in the HCV than in the HBV cohort. In the HCV cohort, ethanol intake was an independent predictor of liver cirrhosis and of death rate in both cohorts. We found no association between baseline NOSA and 8.4-year mortality. We conclude that morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary care populations, blood donors, or clinical series, and that ethanol intake >30 g/day is the most important and evitable risk factor for cirrhosis and death in patients with chronic HCV or HBV infection. Copyright © 2011 S. Karger AG, Basel.

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