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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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Functional characterization of the high-fat responsive genes.Representative overrepresented functional categories in the set of 1663 high-fat responsive genes are grouped according to their biological function: (a) lipid and cholesterol metabolism, (b) oxidative and metabolic processes, (c) inflammatory and immune response, (d) apoptosis and protein folding, (e) cell growth and cell cycle and (f) transcription regulation and signal transduction. For each functional group, representative genes are listed and their expression profiles (average HFBT vs. chow and HFP vs. chow expression ratios per time-point) are shown in the adjacent diagrams.
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pone-0006646-g002: Functional characterization of the high-fat responsive genes.Representative overrepresented functional categories in the set of 1663 high-fat responsive genes are grouped according to their biological function: (a) lipid and cholesterol metabolism, (b) oxidative and metabolic processes, (c) inflammatory and immune response, (d) apoptosis and protein folding, (e) cell growth and cell cycle and (f) transcription regulation and signal transduction. For each functional group, representative genes are listed and their expression profiles (average HFBT vs. chow and HFP vs. chow expression ratios per time-point) are shown in the adjacent diagrams.

Mentions: To identify which cellular processes are most affected by the hepatic exposure to excess dietary fat over the entire time-course, we first analyzed the overrepresented functional categories among the 1663 HF-responsive genes [29]. The most prominent significantly enriched functional clusters are related to lipid, cholesterol and oxido-reductive metabolism, as well as inflammation, immune response, apoptosis, cell cycle, protein folding and the regulatory pathways controlling these processes (Figure 2, Table S3 (“All HF-responsive genes”)). The expression changes per diet and time-point of the selected representative genes for each functional cluster are also shown in Figure 2. To assess if some of the categories are specifically enriched in either up- or down-regulated genes, we additionally performed the equivalent type of analysis using separately lists of HF-responsive up- and downregulated genes (Table S3 (“Upregulated HF-responsive genes” and “Downregulated HF-responsive genes”)). As a number of genes changed the direction of their regulation between the early and the late phase of the time-course, many categories were represented in both lists. Specifically, the enrichment of lipid metabolism and inflammatory processes were highly significant among the upregulated HF-responsive genes, and glutathione metabolism and cholesterol biosynthesis were most significant among the downregulated HF-responsive genes.


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)

Functional characterization of the high-fat responsive genes.Representative overrepresented functional categories in the set of 1663 high-fat responsive genes are grouped according to their biological function: (a) lipid and cholesterol metabolism, (b) oxidative and metabolic processes, (c) inflammatory and immune response, (d) apoptosis and protein folding, (e) cell growth and cell cycle and (f) transcription regulation and signal transduction. For each functional group, representative genes are listed and their expression profiles (average HFBT vs. chow and HFP vs. chow expression ratios per time-point) are shown in the adjacent diagrams.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2722023&req=5

pone-0006646-g002: Functional characterization of the high-fat responsive genes.Representative overrepresented functional categories in the set of 1663 high-fat responsive genes are grouped according to their biological function: (a) lipid and cholesterol metabolism, (b) oxidative and metabolic processes, (c) inflammatory and immune response, (d) apoptosis and protein folding, (e) cell growth and cell cycle and (f) transcription regulation and signal transduction. For each functional group, representative genes are listed and their expression profiles (average HFBT vs. chow and HFP vs. chow expression ratios per time-point) are shown in the adjacent diagrams.
Mentions: To identify which cellular processes are most affected by the hepatic exposure to excess dietary fat over the entire time-course, we first analyzed the overrepresented functional categories among the 1663 HF-responsive genes [29]. The most prominent significantly enriched functional clusters are related to lipid, cholesterol and oxido-reductive metabolism, as well as inflammation, immune response, apoptosis, cell cycle, protein folding and the regulatory pathways controlling these processes (Figure 2, Table S3 (“All HF-responsive genes”)). The expression changes per diet and time-point of the selected representative genes for each functional cluster are also shown in Figure 2. To assess if some of the categories are specifically enriched in either up- or down-regulated genes, we additionally performed the equivalent type of analysis using separately lists of HF-responsive up- and downregulated genes (Table S3 (“Upregulated HF-responsive genes” and “Downregulated HF-responsive genes”)). As a number of genes changed the direction of their regulation between the early and the late phase of the time-course, many categories were represented in both lists. Specifically, the enrichment of lipid metabolism and inflammatory processes were highly significant among the upregulated HF-responsive genes, and glutathione metabolism and cholesterol biosynthesis were most significant among the downregulated HF-responsive genes.

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