Hepatic Expression Patterns of Inflammatory and Immune Response Genes Associated with Obesity and NASH in Morbidly Obese Patients

Bertola, Adeline; Bonnafous, Stéphanie; Anty, Rodolphe; Patouraux, Stéphanie; Saint–Paul, Marie–Christine; Iannelli, Antonio; Gugenheim, Jean; Barr, James; Mato, José M.; Marchand-Brustel, Y. Le; Tran, Albert; Gual, Philippe

doi:10.1371/journal.pone.0013577

Cited by 210 publications

(200 citation statements)

References 56 publications

(59 reference statements)

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“…Recent evidence involving morbidly obese patients with NASH etiology has been strongly associated with a specific increase in the liver expression of a wide array of proinflammatory M1 cytokines, especially IL-1b (Bertola et al, 2010). Recent reports from our laboratory have shown that CYP2E1-induced oxidative stress causes up-regulation of pattern recognition receptor P2X7r (purinergic receptor X7), which has a direct role in activation of T H 1 cells (Das et al, 2013b).…”

Section: Resultsmentioning

confidence: 99%

“…This happens mostly in the initial phases of liver injury in rodent models, which have been used to study NASH progression. Patients with early phases of NASH occurrences also have reciprocated an M1 bias (Bertola et al, 2010). However, NASH progression is also associated with a delayed shift into profibrotic mechanisms, which might require an M2 polarization.…”

Section: Introductionmentioning

confidence: 99%

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M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

Seth

Das

Pourhoseini

et al. 2014

J Pharmacol Exp Ther

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Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1b (IL-1b) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl 3 ), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASHabrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

Seth

Das

Pourhoseini

et al. 2014

J Pharmacol Exp Ther

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“…obesity-related gene expression changes in NAFLD in addition to inflammatory and immune system components of the liver (Baranova et al, 2005;Younossi et al, 2005b;Bertola et al, 2010). However, there is a lack of studies on expression changes of genes related to the absorption, distribution, metabolism, and elimination (ADME) processes in progressive human NAFLD.…”

Section: Introductionmentioning

confidence: 99%

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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“…Since we and others have found that CCL2 is also elevated in patients with alcoholic hepatitis and NASH (Fig. 1C) (7)(8)(9), although significantly lower than in HCV infection, it is possible that parallel gene-regulatory mechanisms may operate in non-HCV-mediated liver diseases.…”

Section: Discussionmentioning

confidence: 78%

“…CCL2, or monocyte chemotactic protein 1, is a cytokine (11 kDa) of the CC chemokine family secreted by a variety of cell types, including fibroblasts; peripheral blood mononuclear cells; monocytes; macrophages; and epithelial, endothelial, smooth muscle, and dendritic and microglial cells (3)(4)(5)(6). CCL2 is upregulated in patients with chronic liver diseases, such as alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), and HCV infection, which are accompanied by inflammation (7)(8)(9). In mice, removal of the cytokine interleukin-6 (IL-6) and components of the IL-6 receptor (IL-6R) complex and STAT3 impairs CCL2 expression (10).…”

mentioning

confidence: 99%

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Sarma

Tiriveedhi

Crippin

et al. 2014

J Virol

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Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBP␣, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBP␣, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBP␣. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis. IMPORTANCEHepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.

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Hepatic Expression Patterns of Inflammatory and Immune Response Genes Associated with Obesity and NASH in Morbidly Obese Patients

Cited by 210 publications

References 56 publications

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

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

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

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