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| 1 | Liver enzymes,metabolomics and genome-wide association studies:From systems biology to the personalized medicine显示文摘For several decades,serum levels of alanine(ALT) and aspartate(AST) aminotransferases have been regarded as markers of liver injury,including a wide range of etiologies from viral hepatitis to fatty liver.The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes,coronary heart disease,atherothrombotic risk profile,and overall risk of metabolic disease.Therefore,it is plausible to suggest that aminotransferases are surrogate biomarkers of 'liver metabolic functioning' beyond the classical concept of liver cellular damage,as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function.In this study,we summarize the background information and recent findings on the biological role of ALT and AST,and review the knowledge gained from the application of genome-wide approaches and 'omics' technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions.Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes,which suggest that regulation of aminotransferase activity is a complex and highly regulated trait.Finally,links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity. | Silvia Sookoian Carlos J Pirola | 2015 | World Journal of Gastroenterology2015，21，3： | 27 |
| 2 | Alanine and aspartate aminotransferase and glutamine-cycling pathway:Their roles in pathogenesis of metabolic syndrome显示文摘Although new research technologies are constantly used to look either for genes or biomarkers in the prediction of metabolic syndrome(MS),the pathogenesis and pathophysiology of this complex disease remains a major challenge.Interestingly,Cheng et al recently investigated possible pathways underlying MS by high-throughput metabolite profiling in two large and well characterized community-based cohorts.The authors explored by liquid chromatography and mass spectrometry the plasma concentrations of 45 distinct metabolites and examined their relation to cardiometabolic risk,and observed that metabolic risk factors such as obesity,insulin resistance(IR),high blood pressure,and dyslipidemia were associated with several metabolites,including branched-chain amino acids,other hydrophobic amino acids,tryptophan breakdown products,and nucleotide metabolites.In addition,the authors found a significant association of IR traits with glutamine,glutamate and the glutamineto-glutamate ratio.These data provide new insight into the pathogenesis of MS-associated phenotypes and introduce a crucial role of glutamine-cycling pathway as prominently involved in the development of metabolic risk.We consider that the hypothesis about the role of abnormal glutamate metabolism in the pathogenesis of the MS is certainly challenging and suggests the critical role of the liver in the global metabolic modulation as glutamate metabolism is linked with aminotransferase reactions.We discuss here the critical role of the 'liver metabolism' in the pathogenesis of the MS and IR,and postulate that before fatty liver develops,abnormal levels of liver enzymes,such as alanine and aspartate aminotransferases might reflect high levels of hepatic transamination of amino acids in the liver. | Silvia Sookoian Carlos J Pirola | 2012 | World Journal of Gastroenterology2012，18，29： | 11 |
| 3 | Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity显示文摘This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer. | Carlos J Pirola Silvia Sookoian | 2018 | World Journal of Gastroenterology2018，24，15： | 8 |
| 4 | PNPLA3,the triacylglycerol synthesis/hydrolysis/storage dilemma,and nonalcoholic fatty liver disease显示文摘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 glycerol3-phosphate acyltransferase 2 is suggested by data miming. | Silvia Sookoian Carlos J Pirola | 2012 | World Journal of Gastroenterology2012，18，42： | 7 |
| 5 | Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: A pilot study显示文摘AIM: To evaluate the safety and efficacy of chronic administration of losartan on hepatic fibrosis in chronic hepatitis C patients. METHODS: Fourteen patients with chronic hepatitis C non-responders (n = 10), with contraindications (n = 2) or lack of compliance (n = 2) to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after losartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies (interval 6-14 mo). Histological activity index (HAI) with fibrosis stage was assessed under blind conditions by means of Ishak's score. Subendothelial fibrosis was evaluated by digital image analyses. RESULTS: The changes in the fibrosis stage were significantly different between losartan group (decrease of 0.5±1.3) and controls (increase of 0.89±1.27; P<0.03). In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients (P<0.04). A decrease in sub-endothelial fibrosis was observed in the losartan group. No differences were found in HAI after losartan administration. Acute and chronic decreases in systolic arterial pressures (P<0.05) were observed after the losartan administration, without changes in mean arterial pressure or renal function. CONCLUSION: Chronic AT-Ⅱ type 1 receptor (AT1R) blockade may reduce liver fibrosis in patients with chronic hepatitis C. | Silvia Sookoian María Alejandra Fernández Gustavo Casta(n|~)o | 2005 | World Journal of Gastroenterology2005，11，48： | 7 |
| 6 | Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease显示文摘AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity. METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r2 > 0.8) were genotyped. RESULTS: rs11932595 and rs6843722 showed signifi cant associations with NAFLD (empiric P = 0.0449 and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722 (empiric P = 0.0229) and rs6850524 (empiric P = 0.00899) and between fibrosis score and rs1554483 (empiric P = 0.02697), rs6843722 (empiric P = 0.01898) and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097). CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes insusceptibility to NAFLD and disease severity. | Silvia Sookoian Gustavo Castao Carolina Gemma Tomas Fernández Gianotti Carlos Jose Pirola | 2007 | World Journal of Gastroenterology2007，13，31： | 5 |
| 7 | Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy显示文摘The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants. | Silvia Sookoian Gustavo Castao Carlos J Pirola | 2008 | World Journal of Gastroenterology2008，14，13： | 4 |
| 8 | Obstructive Sleep Apnea Is Associated with Fatty Liver and Abnormal Liver Enzymes: a Meta-analysis显示文摘 | Silvia Sookoian Carlos J. Pirola | 2013 | Obesity Surgery2013，，11： | 3 |
| 9 | The Genetic Epidemiology of Nonalcoholic Fatty Liver Disease显示文摘 | Silvia Sookoian Carlos J. Pirola | 2012 | Clinics in Liver Disease2012，，3： | 3 |
| 10 | Acute hepatitis C in a chronically HIV-infected patient:Evolution of different viral genomic regions显示文摘AIM: To analyze the molecular evolution of different viral genomic regions of HCV in an acute HCV infected patient chronically infected with HIV through a 42-month follow-up.METHODS: Serum samples of a chronically HIV infected patient that seroconverted to anti HCV antibodies were sequenced, from the event of superinfection through a period of 17 months and in a late sample (42nd month). Hypervariable genomic regions of HIV (V3 loop of the gp120) and HCV (HVR-1 on the E2 glycoprotein gene) were studied. In order to analyze genomic regions involved in different biological functions and with the cellular immune response, HCV core and NS5A were also chosen to be sequenced. Amplification of the different regions was done by RT-PCR and directly sequenced. Confirmation of sequences was done on reamplified material. Nucleotide sequences of the different time points were aligned with CLUSTAL W 1.5, and the corresponding amino acid ones were deduced.RESULTS: Hypervariable genomic regions of both viruses (HVR1 and gp120 V3 loop) presented several nonsynonymous changes but, while in the gp120 V3 loop mutations were detected in the sample obtained right after HCV superinfection and maintained throughout, they occurred following a sequential and cumulative pattern in the HVR1. In the NS5A region of HCV, two amino acid changes were detected during the follow-up period, whereas the core region presented several amino acid replacements, once the HCV chronic infection had been established.CONCLUSION: During the HIV-HCV superinfection, each genomic region analyzed shows a different evolutionary pattem.Most of the nucleotide substitutions observed are nonsynonymous and clustered in previously described epitopes,thus suggesting an immune-driven evolutionary process. | Diego Flichman Veronica Kott Silvia Sookoian Rodolfo Campos | 2003 | World Journal of Gastroenterology2003，9，7： | 2 |
| 11 | Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system显示文摘Genome-wide association studies of complex diseases,including nonalcoholic fatty liver disease(NAFLD),have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits—a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies.We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD.We used information retrieved from large public National Health and Nutrition Examination Surveys,Genome-wide association studies,and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits.Next,we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis,and genes that modulate hematological-related traits—specifically platelet count.We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets.Genes associated with platelet count are most highly expressed in the liver,followed by the pancreas,heart,and muscle.Conversely,genes associated with NAFLD presented high expression levels in the brain,lung,spleen,and colon.Functional mapping,gene prioritization,and functional analysis of the most significant loci(P<1×10-8)revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways.In conclusion,variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits,particularly platelet count.Likewise,significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways.Hence,this approach yields novel mechanistic insights into NAFLD pathogenesis. | Carlos Jose Pirola Adrian Salatino Silvia Sookoian | 2021 | World Journal of Gastroenterology2021，27，4： | 2 |
| 12 | Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: A systematic review显示文摘 | Silvia Sookoian Carlos J. Pirola | 2008 | Journal of Hepatology2008，，4： | 2 |
| 13 | Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease显示文摘 | Carlos Jose Pirola Tomas Fernández Gianotti Adriana Laura Burgue?o Manuel Rey-Funes Cesar Fabian Loidl Pablo Mallardi Julio San Martino Gustavo Osvaldo Casta?o S Sookoian | 2013 | Gut2013，，9： | 2 |
| 14 | Cardiovascular and Systemic Risk in Nonalcoholic Fatty Liver Disease - Atherosclerosis as a Major Player in the Natural Course of NAFLD显示文摘 | Amedeo Lonardo Silvia Sookoian Michel Chonchol Paola Loria Giovanni Targher | 2013 | Current Pharmaceutical Design2013，，29： | 2 |
| 15 | A decreased mitoehondrial DNA content is related to insulin resistance in adolescents显示文摘 | Gianotti T F Sookoian S Dieuzeide G | 2008 | Obesity (Silver Spring)2008，16，7： | 1 |
| 16 | Association of the C- 344T aldosterone synthase gene variant with essential hypertension : a meta- analysis 显示文摘 | Sookoian S Gianotti TF Gonzalez CD Pirola CJ | 2007 | J Hypertens2007，25，1： | 1 |
| 17 | Methylation of TFAM gene promoter in peripheral white blood cells is associated with insulin resistance in adolescents显示文摘 | Gemma C Sookoian S Dieuzeide G | | 0，，01： | 1 |
| 18 | A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity 显示文摘 | Sookoian S Castano GO Burgueno AL | 2009 | J Lipid Res2009，50，10： | 1 |
| 19 | A1166C angiotenain Ⅱ type 1 receptor gene polymorphism may predict hemodynamic response to losartan in patients with cirrhosis and portal hypertension显示文摘 | Sookoian S Castano G Garcia SI | 2005 | Am J Gastroenterol2005，100，3： | 1 |
| 20 | Association of theC-344T aldosterone synthase gene variant with essential hyper-tension: a meta-analysis显示文摘 | Sookoian S Gianotti TF Gonzalez CD | 2007 | J Hypertens2007，25，1： | 1 |
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