Authors: Burgueño, Adriana Laura; Fernandez Gianotti, Tomas; Gonzales Mansilla, Noelia Luz; Pirola, Carlos Jose; Sookoian, Silvia Cristina
Publication Date: 2013.
Language: English.
Abstract:
CVD (cardiovascular disease) is associated with abnormal liver enzymes, and NAFLD (non-alcoholic fatty liver disease) is independently associated with cardiovascular risk. To gain insights into the molecular events underlying the association between liver enzymes and CVD, we developed an HFD (high-fat diet)-induced NAFLD in the SHR (spontaneously hypertensive rat) and its control WKY (Wistar–Kyoto) rat strain. We hypothesized that hepatic induction of Hif1a (hypoxia-inducible factor 1α) might be the link between CVD and liver injury. Male SHRs (n=13) and WKY rats (n=14) at 16 weeks of age were divided into two experimental groups: standard chow diet and HFD (10 weeks). HFD-fed rats, irrespective of the strain, developed NAFLD; however, only HFD-SHRs had focus of lobular inflammation and high levels of hepatic TNFα (tumour necrosis factor α). SHRs had significantly higher liver weight and ALT (alanine aminotransferase) levels, irrespective of NAFLD. Liver abundance of Hif1a mRNA and Hif1α protein were overexpressed in SHRs (P<0.04) and were significantly correlated with ALT levels (R=0.50, P<0.006). This effect was not reverted by a direct acting splanchnic vasodilator (hydralazine). Angiogenesis may be induced by the HFD, but the disease model showed significantly higher hepatic Vegf (vascular endothelial growth factor) levels (P<0.025) even in absence of dietary insult. Hif1a mRNA overexpression was not observed in other tissues. Liver mRNA of Nr1d1 (nuclear receptor subfamily 1, group D, member 1; P<0.04), Ppara [Ppar (peroxisome-proliferatoractivated receptor) α; P<0.05], Pparg (Pparγ; P<0.001) and Sirt1 (Sirtuin 1; P<0.001) were significantly upregulated in SHRs, irrespective of NAFLD. Sirt1 and Hif1a mRNAs were significantly correlated (R=0.71, P<0.00002). In conclusion, CVD is associated with Hif1a-related liver damage, hepatomegaly and reprogramming of liver metabolism, probably to compensate metabolic demands.
Author affiliation: Burgueño, Adriana Laura. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina
Author affiliation: Fernandez Gianotti, Tomas. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Gonzales Mansilla, Noelia Luz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Pirola, Carlos Jose. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Pirola, Carlos Jose; Fernandez Gianotti, Tomas; Castaño, Gustavo Osvaldo; Mallardi, Pablo; San Martino, Julio; González López Ledesma, María Mora; Flichman, Diego Martin; Mirshahi, Faridodin; Sanyal, Arun J.; Sookoian, Silvia Cristina
Publication Date: 2014.
Language: English.
Abstract:
OBJECTIVES: We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome. METHODS: The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls. RESULTS: Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity. CONCLUSIONS: miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.
Author affiliation: Pirola, Carlos Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Fernandez Gianotti, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Mallardi, Pablo. Hospital Diego Thompson; Argentina
Author affiliation: San Martino, Julio. Hospital Diego Thompson; Argentina
Author affiliation: González López Ledesma, María Mora. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina
Author affiliation: Mirshahi, Faridodin. Virginia Commonwealth University; Estados Unidos
Author affiliation: Sanyal, Arun J.. Virginia Commonwealth University; Argentina
Author affiliation: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Bay, Maria Luisa; Cañero Velasco, Cristina; Ciocca, Mirta; Cotti, Andrea; Cuarterolo, Miriam; Fainboim, Alejandro; Fassio, Eduardo; Galoppo, Marcela; Piñero, Federico; Rozenfeld, Paula Adriana
Publication Date: 2017.
Language: Spanish.
Abstract:
Lysosomal acid lipase deficiency (LAL-D) is stilla little recognized genetic disease with significantmorbidity and mortality in children and adults.This document provides guidance on whento suspect LAL-D and how to diagnose it. Itis recommended to add lysosomal acid lipasedeficiency to the list of differential diagnoses ofsepsis, oncological diseases, storage diseases,persistent diarrhea, chronic malnutrition, andhemophagocytic lymphohistiocytosis. It shouldalso be considered in young patients withdyslipidemia and atherosclerosis as well as diseasesassociated with fatty liver and/or hepatomegaly.LAL-D should be suspected in patients withhepatomegaly, hyperlipidemia and/or elevatedtransaminases found during routine checks ortesting for other conditions, and in patientswith cryptogenic cirrhosis. At present, thereis the option of a specific enzyme replacementtreatment.
Author affiliation: Bay, Maria Luisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Author affiliation: Cañero Velasco, Cristina. Hospital de Niños de San Justo; Argentina
Author affiliation: Ciocca, Mirta. Hospital Alemán; Argentina
Author affiliation: Cotti, Andrea. Hospital Universitario Austral; Argentina
Author affiliation: Cuarterolo, Miriam. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Author affiliation: Fainboim, Alejandro. Hospital de Niños Ricardo Gutiérrez; Argentina
Author affiliation: Fassio, Eduardo. Hospital Nacional Prof. Alejandro Posadas; Argentina
Author affiliation: Galoppo, Marcela. Hospital de Niños Ricardo Gutiérrez; Argentina
Author affiliation: Piñero, Federico. Hospital Universitario Austral; Argentina
Author affiliation: Rozenfeld, Paula Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Lucero, Diego Martín; Miksztowicz, Verónica Julieta; Gualano, Gisela; Longo, Cristina; Landeira, Graciela; Álvarez, Estela; Zago, Valeria; Brites, Fernando Daniel; Berg, Gabriela Alicia; Fassio, Eduardo; Schreier, Laura Ester
Publication Date: 2017.
Language: English.
Abstract:
Background We evaluated possible changes in VLDLcharacteristics, and metabolic related factors, in MetS-associated NAFLD and accompanying liver fibrosis. Methods We studied 36 MetS patients with biopsy-proven NAFLD (MetS + NAFLD) and 24 MetS without ultrasound NAFLD evidence. Further, MetS + NAFLD was sub-divided according to fibrosis stage into, non-to-moderate (F0–F2, n = 27) and severe (F3–F4, n = 9) fibrosis. We measured: lipid profile, VLDL composition and size (size exclusion-HPLC), CETP and lipoprotein lipase (LPL) activities and adiponectin. Additionally, in MetS + NAFLD type IV collagen 7S domain was measured. Results MetS + NAFLD showed increased VLDL-mass, VLDL particle number, VLDL-triglyceride% and large VLDL-% (p < 0.04). CETP activity tended to increase in MetS + NAFLD (p = 0.058), while LPL activity was unchanged. Moreover, in MetS + NAFLD, adiponectin was decreased (p < 0.001), and negatively correlated with VLDL-mass and VLDL particle number (p < 0.05), independently of insulin-resistance. Within MetS + NAFLD group, despite greater insulin-resistance, patients with severe fibrosis showed lower plasma triglycerides, VLDL-mass, VLDL-triglyceride%, large VLDL-% and CETP activity (p < 0.05), while type IV collagen was increased (p = 0.009) and inversely correlated with large VLDL-% (p = 0.045). Conclusions In MetS, NAFLD is associated with larger and triglyceride over-enriched circulating VLDLs, of greater atherogenicity. However, when NAFLD progresses to severe fibrosis, circulating VLDL features apparently improved, probably due to early alterations in hepatic synthetic function.
Author affiliation: Lucero, Diego Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Author affiliation: Miksztowicz, Verónica Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Author affiliation: Gualano, Gisela. Hospital Nacional “Profesor Alejandro Posadas”; Argentina
Author affiliation: Longo, Cristina. Hospital Nacional “Profesor Alejandro Posadas”; Argentina
Author affiliation: Landeira, Graciela. Hospital Nacional “Profesor Alejandro Posadas”; Argentina
Author affiliation: Álvarez, Estela. Hospital Nacional “Profesor Alejandro Posadas”; Argentina
Author affiliation: Zago, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Author affiliation: Brites, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Author affiliation: Berg, Gabriela Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Author affiliation: Fassio, Eduardo. Hospital Nacional “Profesor Alejandro Posadas”; Argentina
Author affiliation: Schreier, Laura Ester. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Publication Date: 2015.
Language: English.
Abstract:
Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of triglycerides (TGs) within hepatocytes exceeding 5 % of liver weight. NAFLD is a spectrum of pathological processes from nonalcoholic fatty liver or simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. As NAFLD induces metabolic syndrome (MS), then, NAFLD is associated with insulin resistance (IR), type 2 diabetes mellitus (T2DM), hypertension and even Polycystic Ovary Syndrome (PCOS). Because it is well established that patients carrying gene mutations also develop NAFLD in the absence of IR, the genetic predisposition to NAFLD is also discussed. Little is known about the diagnosis and treatment of NAFLD in children and adolescents and the lack of non-invasive diagnostic tools in these populations is a major problem faced by physicians. The present review aims to discuss recent findings of NAFLD in children and adolescents and, considering the features in common with PCOS, we also discuss their relationship.
Author affiliation: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Author affiliation: Motta, Alicia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Valva, Pamela; Rios, Daniela Alejandra; Casciato, Paola; Gadano, Adrián Carlos; Galdame, Omar; Mullen, Eduardo; Bertot, Gustavo; de Matteo, Elena Noemí; Preciado, María Victoria
Publication Date: 2017.
Language: English.
Abstract:
Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has been increasing constantly and linked to the global obesity epidemic. The NAFLD histologic spectrum ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Liver biopsy is the only reliable means to diagnose and stage NASH, but its invasive nature limits its use. Therefore, the prediction of hepatic injury by means of the development of new noninvasive tests represents a growing medical need. Our aim was to evaluate matrix deposition and cell-death markers, which correlate with liver injury in an NAFLD patient cohort. Patients and methods Liver biopsies and serum from 34 NAFLD adult patients were analyzed. Histological parameters were evaluated. Matrix deposition [hyaluronic acid (HA) and tissue inhibitor of matrix metalloproteinase inhibitor-1 (TIMP-1)] and cell-death markers [cytokeratin-18 (M65) and caspase-cleaved cytokeratin-18 (M30)] were measured in serum samples. Results HA showed an association with fibrosis severity (P=0.03) and M30 with steatosis (P=0.013), inflammation (P=0.004), and fibrosis severity (P=0.04). In contrast, TIMP-1 and M65 showed no association with any histological parameter of liver injury. The evaluation of diagnostic accuracy showed good performance as less invasive markers of significant fibrosis of both HA (area under the receiver operating characteristic curve: 0.928) and M30 (area under the receiver operating characteristic curve: 0.848). Conclusion Biomarkers are essential tools that may provide a quick and accurate diagnosis for patients with life-threatening NAFLD and NASH. HA and M30, together or determined sequentially, have been found to be straightforward tests that may be sufficient to predict significant fibrosis even in a primary care center of an underdeveloped country.
Author affiliation: Valva, Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina
Author affiliation: Rios, Daniela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina
Author affiliation: Casciato, Paola. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Gadano, Adrián Carlos. Hospital Italiano; Argentina
Author affiliation: Galdame, Omar. Hospital Italiano; Argentina
Author affiliation: Mullen, Eduardo. Hospital Italiano; Argentina
Author affiliation: Bertot, Gustavo. Instituto Universidad de la Fundación "Héctor Barceló"; Argentina
Author affiliation: de Matteo, Elena Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina
Author affiliation: Preciado, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Sookoian, Silvia Cristina; Puri, Puneet; Castaño, Gustavo Osvaldo; Scian, Romina; Mirshahi, Faridodin; Sanyal, Arun J.; Pirola, Carlos José
Publication Date: 2017.
Language: English.
Abstract:
Background and Aims: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, which includes changes in the liver methylome. Betaine plays a pivotal role in the regulation of methylogenesis. We performed a two-stage case–control study, which included patients with biopsy-proven NAFLD to explore circulating levels of betaine and its association with the histological spectrum. We also explored the association between a missense rs1805074, p.Ser646Pro variant in DMGDH (dimethylglycine dehydrogenase mitochondrial) and NAFLD severity (n=390). Results: In the discovery phase (n=48), betaine levels were associated with the disease severity (P=.0030), including liver inflammation (Spearman R:−0.51, P=.001), ballooning degeneration (R: −0.50, P=.01) and fibrosis (R: −0.54, P=.0008). Betaine levels were significantly decreased in nonalcoholic steatohepatitis (NASH) in comparison with nonalcoholic fatty liver (NAFL). Further replication (n=51) showed that betaine levels were associated with advanced NAFLD (P=.0085), and patients with NASH had a 1.26-fold decrease in betaine levels compared with those with NAFL. The rs1805074 was significantly associated with the disease severity (P=.011). Conclusion: NAFLD severity is associated with a state of betaine-insufficiency.
Author affiliation: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Puri, Puneet. Virginia Commonwealth University School of Medicine; Estados Unidos
Author affiliation: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Author affiliation: Scian, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Mirshahi, Faridodin. Virginia Commonwealth University School of Medicine; Estados Unidos
Author affiliation: Sanyal, Arun J.. Virginia Commonwealth University School of Medicine; Estados Unidos
Author affiliation: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Keywords: BETAINE; BIOMARKERS; DIMETHYLGLYCINE DEHYDROGENASE MITOCHONDRIAL; DNA METHYLATION; EPIGENETICS; FIBROSIS; GENETICS; INFLAMMATION; METABOLOMICS; NONALCOHOLIC FATTY LIVER DISEASE; NONALCOHOLIC STEATOHEPATITIS; Inmunología; Medicina Básica; CIENCIAS MÉDICAS Y DE LA SALUD; Medicina Critica y de Emergencia; Medicina Clínica; CIENCIAS MÉDICAS Y DE LA SALUD.
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Sookoian, Silvia Cristina; Pirola, Carlos José
Publication Date: 2012.
Language: English.
Abstract:
Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease (NAFLD). However, the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3 (PNPLA3, also known as adiponutrin). A nonsynonymous single nucleotide polymorphism in PNPLA3 (rs738409 C/G, a coding variant that encodes an amino acid substitution I148M) is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogenesis/ lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3' UTR region (hsa-miR-769-3p and hsa-miR-516a-3p). In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, corroborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol- 3-phosphate acyltransferase 2 is suggested by data miming. © 2012 Baishideng. All rights reserved.
Author affiliation: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Author affiliation: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Terra, Ximena; Auguet, Teresa; Broch, Montserrat; Sabench, Fátima; Hernandez, Mercè; Pastor, Rosa M.; Quesada, Isabel María; Lunna, Ana; Aguilar, Carmen; Del Castillo, Daniel; Richard, Cristobal
Publication Date: 2013.
Language: English.
Abstract:
We aimed to analyze the retinol binding protein-4 (RBP4) messenger RNA (mRNA) expression profiles in adipose tissues and liver of morbidly obese (MO) women with or without nonalcoholic fatty liver disease (NAFLD), and to study the relationships with other pro- and anti-inflammatory adipokines in vivo and in vitro. We performed a cross-sectional analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver samples from four lean and 45 MO women with or without NAFLD by enzyme-linked immunosorbent assay and real-time reverse transcription-PCR. We also studied RBP4 expression in HepG2 hepatocytes under various inflammatory stimuli. Circulating RBP4 levels were higher in MO women, and specifically, in MO subjects with NAFLD compared with normal liver controls (lean and MO). RBP4 liver expression was higher in nonalcoholic steatohepatitis (NASH)-moderate/severe than in NASHmild. Overall RBP4 gene expression was higher in liver than in adipose tissues. Among them, the higher expression corresponded to SAT. VAT expression was lower in the MO cohort. In HepG2, RBP4 mRNA expression was reduced by tumor necrosis factor (TNF)-α and increased by adiponectin treatment. In conclusion, the results obtained in MO women with NAFLD, brings up the use of RBP4 and other adipokines as a panel of noninvasive molecular biomarkers when NAFLD is suspected. Further studies are needed with other obesity groups.
Author affiliation: Terra, Ximena. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España
Author affiliation: Auguet, Teresa. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España. Hospital Universitari Joan XXIII. Servei Medicina Interna,; España
Author affiliation: Broch, Montserrat. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España
Author affiliation: Sabench, Fátima. Hospital Sant Joan de Reus. Servei de Cirurgia,; España
Author affiliation: Hernandez, Mercè. Hospital Sant Joan de Reus. Servei de Cirurgia,; España
Author affiliation: Pastor, Rosa M.. Hospital Universitari Joan XXIII. Laboratori de Bioquímica; España
Author affiliation: Quesada, Isabel María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España
Author affiliation: Lunna, Ana. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España
Author affiliation: Aguilar, Carmen. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España
Author affiliation: Del Castillo, Daniel. Hospital Sant Joan de Reus. Servei de Cirurgia, ; España
Author affiliation: Richard, Cristobal. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España. Hospital Universitari Joan XXIII. Servei Medicina Interna,; España
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Publication Date: 2016.
Language: English.
Abstract:
The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-Alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.
Author affiliation: Chackelevicius, Carla Melisa. Fondazione Italiana Fegato; Italia
Author affiliation: Gambaro, Sabrina Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Author affiliation: Tiribelli, Claudio. Fondazione Italiana Fegato; Italia
Author affiliation: Rosso, Natalia. Fondazione Italiana Fegato; Italia
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas