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Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients.

Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, Gugenheim J, Barr J, Mato JM, Le Marchand-Brustel Y, Tran A, Gual P - PLoS ONE (2010)

Bottom Line: Interestingly, serum palmitate, known to activate the TLR pathway, was increased with steatosis.NASH was then characterized by a specific gene signature.These findings help to identify new potential actors of the pathogenesis of NAFLD.

View Article: PubMed Central - PubMed

Affiliation: INSERM U895, Team 8 Hepatic Complications of Obesity, Nice, France.

ABSTRACT

Background: Obesity modulates inflammation and activation of immune pathways which can lead to liver complications. We aimed at identifying expression patterns of inflammatory and immune response genes specifically associated with obesity and NASH in the liver of morbidly obese patients.

Methodology/principal findings: Expression of 222 genes was evaluated by quantitative RT-PCR in the liver of morbidly obese patients with histologically normal liver (n = 6), or with severe steatosis without (n = 6) or with NASH (n = 6), and in lean controls (n = 5). Hepatic expression of 58 out of 222 inflammatory and immune response genes was upregulated in NASH patients. The most notable changes occurred in genes encoding chemokines and chemokine receptors involved in leukocyte recruitment, CD and cytokines involved in the T cell activation towards a Th1 phenotype, and immune semaphorins. This regulation seems to be specific for the liver since visceral adipose tissue expression and serum levels of MCP1, IP10, TNFα and IL6 were not modified. Importantly, 47 other genes were already upregulated in histologically normal liver (e.g. CRP, Toll-like receptor (TLR) pathway). Interestingly, serum palmitate, known to activate the TLR pathway, was increased with steatosis.

Conclusion/significance: The liver of obese patients without histological abnormalities already displayed a low-grade inflammation and could be more responsive to activators of the TLR pathway. NASH was then characterized by a specific gene signature. These findings help to identify new potential actors of the pathogenesis of NAFLD.

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Related in: MedlinePlus

Specific upregulation of genes encoding Th1 cytokines and proteins involved in recognition between APC and T cells in liver of NASH patients.A. The hepatic expression levels of genes were analyzed by real-time quantitative PCR in morbidly obese patients with normal liver histology (S0, n = 6), in morbidly obese patients with severe steatosis (S3, n = 6), and in morbidly obese patients with severe steatosis and NASH (NASH, n = 6). The mRNA levels of genes were normalized to the mRNA levels of RPLP0. Results are expressed relative to the expression levels in S0 patients and expressed as mean±SEM. *P<0.05, compared with S0patients; §P = 0,033. B. Scheme of recognition between APC and T cells.
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pone-0013577-g002: Specific upregulation of genes encoding Th1 cytokines and proteins involved in recognition between APC and T cells in liver of NASH patients.A. The hepatic expression levels of genes were analyzed by real-time quantitative PCR in morbidly obese patients with normal liver histology (S0, n = 6), in morbidly obese patients with severe steatosis (S3, n = 6), and in morbidly obese patients with severe steatosis and NASH (NASH, n = 6). The mRNA levels of genes were normalized to the mRNA levels of RPLP0. Results are expressed relative to the expression levels in S0 patients and expressed as mean±SEM. *P<0.05, compared with S0patients; §P = 0,033. B. Scheme of recognition between APC and T cells.

Mentions: A number of comparisons were then performed to detect genes potentially involved in obesity, liver steatosis and NASH. The first analysis compared expression profiles between NASH and S3 patients. We defined as a NASH specific gene, a gene which was upregulated more than 1.4 fold in NASH patients compared to S3 patients and, evidently, to S0 patients and controls (lean patients without liver disease). 58 genes were upregulated in NASH patients and can be separated into two groups: 38 genes were specifically upregulated in NASH patients (and not in S0 and S3 patients) and 20 genes were upregulated in S0 and S3 patients and further increased in NASH patients (Table 2). Interestingly, as illustrated in Figure 1, 15 genes upregulated in NASH patients encoded chemokines and chemokine receptors involved in leukocyte recruitment including the couples CXCL8/CXCR1; CXCL1, 3/CXCR2; CCL3-5/CCR5 and the chemokines CXCL9-11 and CCL2 (MCP1). In addition, CD62E (E-Selectin) and CD44 which could be involved in leukocyte recruitment into inflammation sites were strongly upregulated in NASH patients (Figure 1). Some of the NASH specific genes encoded cytokines and molecules involved in the interaction and co-stimulation between antigen-presenting cells (APC) and T lymphocytes (Figure 2) leading to T cell activation towards a Th1 phenotype. Indeed, the gene expression levels of CD28, CD80 (B7-1), CD86 (B7-2) and IFNγ, in addition to CD18 (LFA1), CD54 (ICAM1), IL1β, IL6 and TNFα were upregulated only in NASH patients. Moreover, the ratio IL10 versus IFNγ was strongly decreased in NASH patients compared to S3 patients (Figure 2A). Among the other NASH genes, the expression of genes encoding members of the plexin/semaphorin family (PLXNC1; SEMA 4D, 7A and 4A) was also strongly increased in NASH patients (Table 2). We finally confirmed the modification of the expression levels of TNFα, IL6 and CCL2 (MCP1) in NASH patients previously reported by other groups [17]–[20].


Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients.

Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, Gugenheim J, Barr J, Mato JM, Le Marchand-Brustel Y, Tran A, Gual P - PLoS ONE (2010)

Specific upregulation of genes encoding Th1 cytokines and proteins involved in recognition between APC and T cells in liver of NASH patients.A. The hepatic expression levels of genes were analyzed by real-time quantitative PCR in morbidly obese patients with normal liver histology (S0, n = 6), in morbidly obese patients with severe steatosis (S3, n = 6), and in morbidly obese patients with severe steatosis and NASH (NASH, n = 6). The mRNA levels of genes were normalized to the mRNA levels of RPLP0. Results are expressed relative to the expression levels in S0 patients and expressed as mean±SEM. *P<0.05, compared with S0patients; §P = 0,033. B. Scheme of recognition between APC and T cells.
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Related In: Results  -  Collection

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pone-0013577-g002: Specific upregulation of genes encoding Th1 cytokines and proteins involved in recognition between APC and T cells in liver of NASH patients.A. The hepatic expression levels of genes were analyzed by real-time quantitative PCR in morbidly obese patients with normal liver histology (S0, n = 6), in morbidly obese patients with severe steatosis (S3, n = 6), and in morbidly obese patients with severe steatosis and NASH (NASH, n = 6). The mRNA levels of genes were normalized to the mRNA levels of RPLP0. Results are expressed relative to the expression levels in S0 patients and expressed as mean±SEM. *P<0.05, compared with S0patients; §P = 0,033. B. Scheme of recognition between APC and T cells.
Mentions: A number of comparisons were then performed to detect genes potentially involved in obesity, liver steatosis and NASH. The first analysis compared expression profiles between NASH and S3 patients. We defined as a NASH specific gene, a gene which was upregulated more than 1.4 fold in NASH patients compared to S3 patients and, evidently, to S0 patients and controls (lean patients without liver disease). 58 genes were upregulated in NASH patients and can be separated into two groups: 38 genes were specifically upregulated in NASH patients (and not in S0 and S3 patients) and 20 genes were upregulated in S0 and S3 patients and further increased in NASH patients (Table 2). Interestingly, as illustrated in Figure 1, 15 genes upregulated in NASH patients encoded chemokines and chemokine receptors involved in leukocyte recruitment including the couples CXCL8/CXCR1; CXCL1, 3/CXCR2; CCL3-5/CCR5 and the chemokines CXCL9-11 and CCL2 (MCP1). In addition, CD62E (E-Selectin) and CD44 which could be involved in leukocyte recruitment into inflammation sites were strongly upregulated in NASH patients (Figure 1). Some of the NASH specific genes encoded cytokines and molecules involved in the interaction and co-stimulation between antigen-presenting cells (APC) and T lymphocytes (Figure 2) leading to T cell activation towards a Th1 phenotype. Indeed, the gene expression levels of CD28, CD80 (B7-1), CD86 (B7-2) and IFNγ, in addition to CD18 (LFA1), CD54 (ICAM1), IL1β, IL6 and TNFα were upregulated only in NASH patients. Moreover, the ratio IL10 versus IFNγ was strongly decreased in NASH patients compared to S3 patients (Figure 2A). Among the other NASH genes, the expression of genes encoding members of the plexin/semaphorin family (PLXNC1; SEMA 4D, 7A and 4A) was also strongly increased in NASH patients (Table 2). We finally confirmed the modification of the expression levels of TNFα, IL6 and CCL2 (MCP1) in NASH patients previously reported by other groups [17]–[20].

Bottom Line: Interestingly, serum palmitate, known to activate the TLR pathway, was increased with steatosis.NASH was then characterized by a specific gene signature.These findings help to identify new potential actors of the pathogenesis of NAFLD.

View Article: PubMed Central - PubMed

Affiliation: INSERM U895, Team 8 Hepatic Complications of Obesity, Nice, France.

ABSTRACT

Background: Obesity modulates inflammation and activation of immune pathways which can lead to liver complications. We aimed at identifying expression patterns of inflammatory and immune response genes specifically associated with obesity and NASH in the liver of morbidly obese patients.

Methodology/principal findings: Expression of 222 genes was evaluated by quantitative RT-PCR in the liver of morbidly obese patients with histologically normal liver (n = 6), or with severe steatosis without (n = 6) or with NASH (n = 6), and in lean controls (n = 5). Hepatic expression of 58 out of 222 inflammatory and immune response genes was upregulated in NASH patients. The most notable changes occurred in genes encoding chemokines and chemokine receptors involved in leukocyte recruitment, CD and cytokines involved in the T cell activation towards a Th1 phenotype, and immune semaphorins. This regulation seems to be specific for the liver since visceral adipose tissue expression and serum levels of MCP1, IP10, TNFα and IL6 were not modified. Importantly, 47 other genes were already upregulated in histologically normal liver (e.g. CRP, Toll-like receptor (TLR) pathway). Interestingly, serum palmitate, known to activate the TLR pathway, was increased with steatosis.

Conclusion/significance: The liver of obese patients without histological abnormalities already displayed a low-grade inflammation and could be more responsive to activators of the TLR pathway. NASH was then characterized by a specific gene signature. These findings help to identify new potential actors of the pathogenesis of NAFLD.

Show MeSH
Related in: MedlinePlus