Hepatitis: Avila MA

Avila MA, Lu KP. · No affiliation provided · Gastroenterology. · Pubmed #17383439 No free full text.

This publication has no abstract.

Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. · Division of Hepatology and Gene Therapy, CIMA-Universidad de Navarra, Pamplona, Spain. · Ann N Y Acad Sci. · Pubmed #19250206 No free full text.

Abstract: A connection between inflammation and cancer has been long suspected. Epidemiological studies have established that many tumors occur in association with chronic infectious diseases, and it is also known that persistent inflammation in the absence of infections increases the risk and accelerates the development of cancer. One clear example of inflammation-related cancer is hepatocellular carcinoma (HCC). HCC is a type tumor that slowly unfolds on a background of chronic inflammation mainly triggered by exposure to infectious agents (hepatotropic viruses) or to toxic compounds (ethanol). The molecular links that connect inflammation and cancer are not completely known, but evidences gathered over the past few years are beginning to define the precise mechanisms. In this article we review the most compelling evidences on the role of transcription factors such as NF-kappaB and STAT3, cytokines like IL-6 and IL-1alpha, ligands of the EGF receptor and other inflammatory mediators in cancer development, with special emphasis in HCC. The molecular dissection of the pathways connecting the inflammatory reaction and neoplasia will pave the way for better therapies to treat cancers.

Berasain C, Castillo J, Prieto J, Avila MA. · Division of Hepatology and Gene Therapy, CIMA, Universidad de Navarra, Pamplona, Spain. · Liver Int. · Pubmed #17311611 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths. This malignancy is often diagnosed at an advanced state, when most potentially curative therapies are of limited efficacy. In addition, HCC is a type of tumor highly resistant to available chemotherapeutic agents, which leaves HCC patients with no effective therapeutic options and a poor prognosis. From a molecular perspective, HCC is a heterogeneous type of tumor. However, in most cases, HCC emerges on a background of persistent liver injury, inflammation and hepatocellular proliferation, which is characteristic of chronic hepatitis and cirrhosis. Recent studies have revealed that dysregulation of a limited number of growth and survival-related pathways can play a key role in HCC development. The epidermal growth factor receptor (ErbB1) can be bound and activated by a broad family of ligands, and can also engage in extensive cross talk with other signaling pathways. This system is considered as an important defense mechanism for the liver during acute tissue injury; however, accumulating evidences suggest that its chronic stimulation can participate in the neoplastic conversion of the liver. Agents that target the ErbB1 receptor have shown antineoplastic activity in other types of tumors, but their efficacy either alone or in combination with other compounds has just started to be tested in experimental and human HCC. Here, we review the evidences that support the involvement of the ErbB1 in HCC development and that provide a rationale for ErbB1 targeting in HCC prevention and treatment.

Fernández-Irigoyen J, Santamaría E, Sesma L, Muñoz J, Riezu JI, Caballería J, Lu SC, Prieto J, Mato JM, Avila MA, Corrales FJ. · Division of Hepatology and Gene Therapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain. · Proteomics. · Pubmed #16252306 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is the fifth most common neoplasm with more than 500 000 new cases diagnosed yearly. Although major risk factors of HCC are currently known, the identification of biological targets leading to an early diagnosis of the disease is considered one of the priorities of clinical hepatology. In this work we have used a proteomic approach to identify markers of hepatocarcinogenesis in the serum of a knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)), as well as in patients with HCC. Three isoforms of apolipoprotein A-I (Apo A-I) with different pI were identified in murine serum. Isoform 1 is up-regulated in the serum of MAT1A(-/-) mice much earlier than any histological manifestation of liver disease. Further characterization of the differential isoform by electrospray MS/MS revealed specific oxidation of methionine 85 and 216 to methionine sulfoxide while the sequence of the analogous peptides on isoforms 2 and 3 showed the nonoxidized methionine residues. Enrichment of an acidic isoform of Apo A-I was also assessed in the serum of hepatitis B virus patients who developed HCC. Specific oxidation of methionine 112 to methionine sulfoxide and tryptophans 50 and 108 to formylkinurenine were identified selectively in the up-regulated isoform. Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, this selectively oxidized Apo A-I isoform may be considered as a pathological hallmark that may help to the understanding of the molecular pathogenesis of HCC.

Berasain C, Herrero JI, García-Trevijano ER, Avila MA, Esteban JI, Mato JM, Prieto J. · Division of Hepatology and Gene Therapy, Department of Medicine, Clínica Universitaria, University of Navarra, Pamplona, Spain. · Hepatology. · Pubmed #12829997 No free full text.

Abstract: The Wilms' tumor suppressor WT1 is a transcriptional regulator present in the fetal but not in the mature liver. Its expression and functional role in liver diseases remains unexplored. In this study, we analyzed WT1 expression by reverse-transcription polymerase chain reaction (RT-PCR) and by immunohistochemistry in normal and diseased livers. In addition, we performed in vitro studies in isolated rat hepatocytes to investigate WT1 regulation and function. We detected WT1 messenger RNA (mRNA) in 18% of normal livers, 17% of chronic hepatitis with minimal fibrosis, 49% of chronic hepatitis with bridging fibrosis, and 71% of cirrhotic livers. In cirrhosis, WT1 immunoreactivity was localized to the nucleus of hepatocytes. WT1 mRNA abundance correlated inversely with prothrombin time (P =.04) and directly with serum bilirubin (P =.002) and with the MELD score (P =.001) of disease severity. In rats, WT1 expression was present in fetal hepatocytes and in the cirrhotic liver but not in normal hepatic tissue. In vitro studies showed that isolated primary hepatocytes express WT1 when stimulated with transforming growth factor beta (TGF-beta) or when the cells undergo dedifferentiation in culture. Moreover, we found that WT1 down-regulates hepatocyte nuclear factor 4 (HNF-4), a factor that is essential to maintain liver function and metabolic regulation in the mature organ. Hepatic expression of HNF-4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels (P =.001). In conclusion, we show that WT1 is induced by TGF-beta and down-regulates HNF-4 in liver cells. WT1 is reexpressed in the cirrhotic liver in relation to disease progression and may play a role in the development of hepatic insufficiency in cirrhosis.

Santamaria E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, Lu SC, Mato JM, Corrales FJ. · Laboratorio de Proteómica, Genómica y Bioinformática, and División de Hepatologia y Terapia Génica, Facultad de Medicina, Universidad de Navarra, 31008 Pamplona, Spain. · Proc Natl Acad Sci U S A. · Pubmed #12631701 links to  free full text

Abstract: Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A(-/-) expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at approximately 8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase beta-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in obob mice and obese patients who are at risk for nonalcoholic steatohepatitis.

Martínez-Chantar ML, Corrales FJ, Martínez-Cruz LA, García-Trevijano ER, Huang ZZ, Chen L, Kanel G, Avila MA, Mato JM, Lu SC. · Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine, University of Navarra, Pamplona, Spain. · FASEB J. · Pubmed #12060674 links to  free full text

Abstract: In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.