Identification of a gene-pathway associated with non-alcoholic steatohepatitis

Rubio, Ángel; Guruceaga, Elizabeth; Vázquez–Chantada, Mercedes; Sandoval, Juan; Martínez-Cruz, Luis Alfonso; Segura, Víctor; Sevilla, Joseph; Podhorski, Adam; Corrales, Fernando J.; Torres, Luís; Rodríguez, Manuel Sánchez; Aillet, Fabienne; Ariz, Usue; Arrieta, Felix; Caballería, Juan; Martín‐Duce, Antonio; Lu, Shelly C.; Martínez‐Chantar, María Luz; Mato, José M.

doi:10.1016/j.jhep.2006.10.021

Cited by 50 publications

(41 citation statements)

References 39 publications

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“…2; Table 1). These data confirm previous studies that show an accumulation of gene expression changes in NASH (Rubio et al, 2007). The results we present in this study comprehensively analyze ADME gene expression alterations across each of the stages of human NAFLD and demonstrate that progression to NASH, with its accompanying features of the second hit, alters this critical category of genes.…”

Section: Discussionsupporting

confidence: 90%

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Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Lake¹,

et al. 2011

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ABSTRACT:Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups-normal, steatosis, and NASH-was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes downregulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes.

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Section: Discussionsupporting

confidence: 90%

“…Previous studies have examined gene expression changes in human NAFLD livers classified as steatotic (Greco et al, 2008) and in livers classified as NASH using various microarray platforms (Younossi et al, 2005a;Baranova et al, 2007;Rubio et al, 2007). These studies confirm that liver disease status alters gene expression changes.…”

Section: Discussionsupporting

confidence: 56%

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Lake¹,

et al. 2011

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“…Our results indicate that waist circumference, an easily available surrogate marker of visceral adiposity, was strongly correlated with metabolic alterations and severity of steatosis, but not with NASH and liver fibrosis. We conclude that not yet elucidated mechanisms, including genetic factors [18], [19], [20], [21], [22] and [23] not quantifiable by the simple measure of waist circumference, are responsible for liver disease progression in patients with NAFLD and that the risk of severe liver damage should not be underestimated in lean subjects.…”

Section: Discussionmentioning

confidence: 99%

Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity

Fracanzani

Valenti

Bugianesi

et al. 2011

Journal of Hepatology

111

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“…The gene set associated with steatosis further includes genes encoding ligands, binding proteins, transporters, and proliferation and apoptosis regulators ( Table 2 ). Alterations in these genes have also been identifi ed in individuals and animal models of NASH ( 43 ), showing partial common gene signatures in human, mouse, and rat NAFLD.…”

Section: Dysregulated Genes In Isolated Hepatocytes Correlated With Tmentioning

confidence: 99%

A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats

Buqué

Martı́nez

Cano

et al. 2010

Journal of Lipid Research

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Identification of a gene-pathway associated with non-alcoholic steatohepatitis

Cited by 50 publications

References 39 publications

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity

A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats

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