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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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Expression changes of plasma proteins caused by HFBT and HFP high-fat diets.Expression changes of a subset of inflammatory plasma proteins that show trend of early activation coupled with late repression compared to the control condition during the 16-week high-fat (HF) feeding time-course, as measured by multiplex immunoassay. Plotted are average protein expression levels per time point in mice fed chow, HFBT and HFP diets. Statistically significant changes in protein expression of HFBT and HFP fed mice compared to chow fed mice per time-point are marked with asterisk and hash symbol, respectively (p value<0.05). All four proteins are associated with NF-κB activation. (A) Immunoglobulin A, protein that activates NF-κB. (B–D) Beta-2 microglobulin, Interleukin-18 and Macrophage-derived chemokine (CCL22), proteins activated by NF-κB.
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pone-0006646-g007: Expression changes of plasma proteins caused by HFBT and HFP high-fat diets.Expression changes of a subset of inflammatory plasma proteins that show trend of early activation coupled with late repression compared to the control condition during the 16-week high-fat (HF) feeding time-course, as measured by multiplex immunoassay. Plotted are average protein expression levels per time point in mice fed chow, HFBT and HFP diets. Statistically significant changes in protein expression of HFBT and HFP fed mice compared to chow fed mice per time-point are marked with asterisk and hash symbol, respectively (p value<0.05). All four proteins are associated with NF-κB activation. (A) Immunoglobulin A, protein that activates NF-κB. (B–D) Beta-2 microglobulin, Interleukin-18 and Macrophage-derived chemokine (CCL22), proteins activated by NF-κB.

Mentions: The transition from an inflammatory (early) to steatotic (late) transcriptional program in livers of ApoE3L mice observed by gene expression profiling is supported by expression of plasma proteins and liver triglyceride content. A series of inflammatory plasma proteins were quantified by multiplex immunoassay during the complete high-fat feeding time-course (Materials and methods). The transient activation of many inflammation-related proteins has been observed during the early phase of the time-course (data not shown). The levels of plasma proteins likely reflect a systems response of multiple organs to excess dietary fat. Nevertheless, the trend of early activation coupled with late repression, which has been observed in the expression of many hepatic inflammatory genes when HF diets are compared to chow diet, can also be found in the expression of NF-κB-related plasma inflammatory proteins. Examples of such proteins are NF-κB activating protein Immunoglobulin A (Figure 7A) and NF-κB activated proteins Beta-2 Microglobulin, Interleukin-18 and Macrophage-Derived Chemokine (CCL22) (Figure 7B-D) [43]–[47]. The upregulation of Interleukin-18 at week 4 and week 8 under all three dietary conditions is followed by HF-specific repression at the two last time-points (Figure 7C).


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)

Expression changes of plasma proteins caused by HFBT and HFP high-fat diets.Expression changes of a subset of inflammatory plasma proteins that show trend of early activation coupled with late repression compared to the control condition during the 16-week high-fat (HF) feeding time-course, as measured by multiplex immunoassay. Plotted are average protein expression levels per time point in mice fed chow, HFBT and HFP diets. Statistically significant changes in protein expression of HFBT and HFP fed mice compared to chow fed mice per time-point are marked with asterisk and hash symbol, respectively (p value<0.05). All four proteins are associated with NF-κB activation. (A) Immunoglobulin A, protein that activates NF-κB. (B–D) Beta-2 microglobulin, Interleukin-18 and Macrophage-derived chemokine (CCL22), proteins activated by NF-κB.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2722023&req=5

pone-0006646-g007: Expression changes of plasma proteins caused by HFBT and HFP high-fat diets.Expression changes of a subset of inflammatory plasma proteins that show trend of early activation coupled with late repression compared to the control condition during the 16-week high-fat (HF) feeding time-course, as measured by multiplex immunoassay. Plotted are average protein expression levels per time point in mice fed chow, HFBT and HFP diets. Statistically significant changes in protein expression of HFBT and HFP fed mice compared to chow fed mice per time-point are marked with asterisk and hash symbol, respectively (p value<0.05). All four proteins are associated with NF-κB activation. (A) Immunoglobulin A, protein that activates NF-κB. (B–D) Beta-2 microglobulin, Interleukin-18 and Macrophage-derived chemokine (CCL22), proteins activated by NF-κB.
Mentions: The transition from an inflammatory (early) to steatotic (late) transcriptional program in livers of ApoE3L mice observed by gene expression profiling is supported by expression of plasma proteins and liver triglyceride content. A series of inflammatory plasma proteins were quantified by multiplex immunoassay during the complete high-fat feeding time-course (Materials and methods). The transient activation of many inflammation-related proteins has been observed during the early phase of the time-course (data not shown). The levels of plasma proteins likely reflect a systems response of multiple organs to excess dietary fat. Nevertheless, the trend of early activation coupled with late repression, which has been observed in the expression of many hepatic inflammatory genes when HF diets are compared to chow diet, can also be found in the expression of NF-κB-related plasma inflammatory proteins. Examples of such proteins are NF-κB activating protein Immunoglobulin A (Figure 7A) and NF-κB activated proteins Beta-2 Microglobulin, Interleukin-18 and Macrophage-Derived Chemokine (CCL22) (Figure 7B-D) [43]–[47]. The upregulation of Interleukin-18 at week 4 and week 8 under all three dietary conditions is followed by HF-specific repression at the two last time-points (Figure 7C).

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