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Genome-wide mRNA expression analysis of hepatic adaptation to high-fat diets reveals switch from an inflammatory to steatotic transcriptional program.

Radonjic M, de Haan JR, van Erk MJ, van Dijk KW, van den Berg SA, de Groot PJ, Müller M, van Ommen B - PLoS ONE (2009)

Bottom Line: This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases.The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-kappaB and PPARgamma regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat.These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies.

View Article: PubMed Central - PubMed

Affiliation: Nutrigenomics Consortium, Top Institute Food and Nutrition, Wageningen, The Netherlands. marijana.radonjic@tno.nl

ABSTRACT

Background: Excessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood.

Principal findings: To identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-kappaB, NEMO, Akt, PPARgamma and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels.

Conclusions: The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-kappaB and PPARgamma regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat. These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies.

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Molecular network underlying hepatic response to high-fat diets (day 3).The global molecular associations of the high-fat responsive genes are functionally characterized and divided into networks based on the functions and/or diseases that are most significant to the network objects (Ingenuity Pathway Analysis). Depicted is the result of merging the network 1 (Immune Response, Tissue Development, Skeletal and Muscular System Development and Function), network 2 (Cellular Development, Connective Tissue Development and Function, Lipid Metabolism) and network 4 (Hepatic System Disease, Liver Steatosis, Cancer). The overrepresented “Function and disease” (Fx) categories “immune response” and “hepatic steatosis” are overlaid onto resulting network, showing which genes (nodes) are directly involved in these processes. The interactions between nodes that are directly connected to both processes are highlighted in pink. Color coding of the nodes corresponds to the direction of gene expression changes at day 3 in HFBT vs. chow diet comparison (upregulated genes are shown in red and downregulated in green).
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pone-0006646-g004: Molecular network underlying hepatic response to high-fat diets (day 3).The global molecular associations of the high-fat responsive genes are functionally characterized and divided into networks based on the functions and/or diseases that are most significant to the network objects (Ingenuity Pathway Analysis). Depicted is the result of merging the network 1 (Immune Response, Tissue Development, Skeletal and Muscular System Development and Function), network 2 (Cellular Development, Connective Tissue Development and Function, Lipid Metabolism) and network 4 (Hepatic System Disease, Liver Steatosis, Cancer). The overrepresented “Function and disease” (Fx) categories “immune response” and “hepatic steatosis” are overlaid onto resulting network, showing which genes (nodes) are directly involved in these processes. The interactions between nodes that are directly connected to both processes are highlighted in pink. Color coding of the nodes corresponds to the direction of gene expression changes at day 3 in HFBT vs. chow diet comparison (upregulated genes are shown in red and downregulated in green).

Mentions: To further explore the control of and the biological connectivity between the HF-responsive genes, the set of 1663 genes (Figure 1B, 1C, Table S1, Table S2) was used as an input for the network analysis within the Ingenuity Pathway Analysis suite [31]. The networks with the highest significance score (network score equal to or higher than 35) and their associated biological functions are listed in the Table 2. To focus on the interactions between the processes identified as crucial for the transition from early to late hepatic response to excess dietary fat, networks related to immune response, lipid metabolism and hepatic steatosis (networks 1, 2 and 4) were merged for further examination (Figure 4, 5). The network number was limited to three to restrict the size and facilitate the clarity of the resulting network.


Genome-wide mRNA expression analysis of hepatic adaptation to high-fat diets reveals switch from an inflammatory to steatotic transcriptional program.

Radonjic M, de Haan JR, van Erk MJ, van Dijk KW, van den Berg SA, de Groot PJ, Müller M, van Ommen B - PLoS ONE (2009)

Molecular network underlying hepatic response to high-fat diets (day 3).The global molecular associations of the high-fat responsive genes are functionally characterized and divided into networks based on the functions and/or diseases that are most significant to the network objects (Ingenuity Pathway Analysis). Depicted is the result of merging the network 1 (Immune Response, Tissue Development, Skeletal and Muscular System Development and Function), network 2 (Cellular Development, Connective Tissue Development and Function, Lipid Metabolism) and network 4 (Hepatic System Disease, Liver Steatosis, Cancer). The overrepresented “Function and disease” (Fx) categories “immune response” and “hepatic steatosis” are overlaid onto resulting network, showing which genes (nodes) are directly involved in these processes. The interactions between nodes that are directly connected to both processes are highlighted in pink. Color coding of the nodes corresponds to the direction of gene expression changes at day 3 in HFBT vs. chow diet comparison (upregulated genes are shown in red and downregulated in green).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2722023&req=5

pone-0006646-g004: Molecular network underlying hepatic response to high-fat diets (day 3).The global molecular associations of the high-fat responsive genes are functionally characterized and divided into networks based on the functions and/or diseases that are most significant to the network objects (Ingenuity Pathway Analysis). Depicted is the result of merging the network 1 (Immune Response, Tissue Development, Skeletal and Muscular System Development and Function), network 2 (Cellular Development, Connective Tissue Development and Function, Lipid Metabolism) and network 4 (Hepatic System Disease, Liver Steatosis, Cancer). The overrepresented “Function and disease” (Fx) categories “immune response” and “hepatic steatosis” are overlaid onto resulting network, showing which genes (nodes) are directly involved in these processes. The interactions between nodes that are directly connected to both processes are highlighted in pink. Color coding of the nodes corresponds to the direction of gene expression changes at day 3 in HFBT vs. chow diet comparison (upregulated genes are shown in red and downregulated in green).
Mentions: To further explore the control of and the biological connectivity between the HF-responsive genes, the set of 1663 genes (Figure 1B, 1C, Table S1, Table S2) was used as an input for the network analysis within the Ingenuity Pathway Analysis suite [31]. The networks with the highest significance score (network score equal to or higher than 35) and their associated biological functions are listed in the Table 2. To focus on the interactions between the processes identified as crucial for the transition from early to late hepatic response to excess dietary fat, networks related to immune response, lipid metabolism and hepatic steatosis (networks 1, 2 and 4) were merged for further examination (Figure 4, 5). The network number was limited to three to restrict the size and facilitate the clarity of the resulting network.

Bottom Line: This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases.The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-kappaB and PPARgamma regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat.These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies.

View Article: PubMed Central - PubMed

Affiliation: Nutrigenomics Consortium, Top Institute Food and Nutrition, Wageningen, The Netherlands. marijana.radonjic@tno.nl

ABSTRACT

Background: Excessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood.

Principal findings: To identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-kappaB, NEMO, Akt, PPARgamma and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels.

Conclusions: The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-kappaB and PPARgamma regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat. These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies.

Show MeSH
Related in: MedlinePlus