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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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Model of the hepatic physiological response to high-fat diets during the 16-week time-course.The summary of a proposed model for the hepatic physiological changes in response to high-fat diets during the 16-week time-course in ApoE3L mice. The initial perturbation of hepatic homeostasis by excess dietary fat triggers the stress response largely controlled by NF-κB and Akt regulators and manifested in activation of acute phase response, inflammation, immune response, hepatic regeneration-like response and lipotoxicity (day 1 to week 1). Upon prolonged high-fat feeding, liver fails to regain the basal state and consequently shifts to pathological state controlled by PPAR and SREBP regulators and characterized by hepatic lipid accumulation and adipogenic transformation, indicative of hepatic steatosis (late phase, week 8 to week 16). The flagship processes induced at the early and at the late phase are shown in boxes. The transition between the stressed and the pathological hepatic state may be controlled by trans-inhibitory interactions between NF-κB and PPARγ regulators, resulting in the tradeoff between inflammatory and steatotic transcription programs (mid phase, week 2 to week 4). On the systems level, the activation of steatotic program is followed by other metabolic syndrome associated pathologies such as obesity and whole-body insulin resistance.
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pone-0006646-g009: Model of the hepatic physiological response to high-fat diets during the 16-week time-course.The summary of a proposed model for the hepatic physiological changes in response to high-fat diets during the 16-week time-course in ApoE3L mice. The initial perturbation of hepatic homeostasis by excess dietary fat triggers the stress response largely controlled by NF-κB and Akt regulators and manifested in activation of acute phase response, inflammation, immune response, hepatic regeneration-like response and lipotoxicity (day 1 to week 1). Upon prolonged high-fat feeding, liver fails to regain the basal state and consequently shifts to pathological state controlled by PPAR and SREBP regulators and characterized by hepatic lipid accumulation and adipogenic transformation, indicative of hepatic steatosis (late phase, week 8 to week 16). The flagship processes induced at the early and at the late phase are shown in boxes. The transition between the stressed and the pathological hepatic state may be controlled by trans-inhibitory interactions between NF-κB and PPARγ regulators, resulting in the tradeoff between inflammatory and steatotic transcription programs (mid phase, week 2 to week 4). On the systems level, the activation of steatotic program is followed by other metabolic syndrome associated pathologies such as obesity and whole-body insulin resistance.

Mentions: The dynamic functional landscape of the hepatic transcriptional adaptation to excess dietary fat during the 16-week time-course suggests a model in which sequential physiological changes underlie the transition from metabolic stress to metabolic syndrome, summarized in Figure 9. These results provide novel insight into the delicate cross-talk between inflammation and lipid metabolism in controlling the progression of metabolic disease development. It is important to note that the late repression of the hepatic NF-κB driven inflammatory/immune response may not seem in line with the established model of the obesity-associated inflammation, well studied in the adipose tissue [10], [67]. The previously shown association of inflammatory signaling pathways with obesity and hepatic steatosis is the most prominent feature observed in our data. Nevertheless, the assumption that, similar to the situation in adipose tissue, hepatic inflammation is secondary to hepatic steatosis is not supported by our findings [68], [69]. In fact, our results show that the temporal order of events contradicts this assumption, at least during the examined time frame and in our mouse model. Extending the duration of treatment and/or increasing amount of excess dietary fat would likely provoke transitions to further grades of severity in hepatic pathology such as hepatosteatitis, fibrosis, cirrhosis and hepatocellular carcinoma. To fully understand the complex relationship between inflammation and metabolic syndrome, information originating from different organs and at various time points needs to be considered on the systems level [69].


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)

Model of the hepatic physiological response to high-fat diets during the 16-week time-course.The summary of a proposed model for the hepatic physiological changes in response to high-fat diets during the 16-week time-course in ApoE3L mice. The initial perturbation of hepatic homeostasis by excess dietary fat triggers the stress response largely controlled by NF-κB and Akt regulators and manifested in activation of acute phase response, inflammation, immune response, hepatic regeneration-like response and lipotoxicity (day 1 to week 1). Upon prolonged high-fat feeding, liver fails to regain the basal state and consequently shifts to pathological state controlled by PPAR and SREBP regulators and characterized by hepatic lipid accumulation and adipogenic transformation, indicative of hepatic steatosis (late phase, week 8 to week 16). The flagship processes induced at the early and at the late phase are shown in boxes. The transition between the stressed and the pathological hepatic state may be controlled by trans-inhibitory interactions between NF-κB and PPARγ regulators, resulting in the tradeoff between inflammatory and steatotic transcription programs (mid phase, week 2 to week 4). On the systems level, the activation of steatotic program is followed by other metabolic syndrome associated pathologies such as obesity and whole-body insulin resistance.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006646-g009: Model of the hepatic physiological response to high-fat diets during the 16-week time-course.The summary of a proposed model for the hepatic physiological changes in response to high-fat diets during the 16-week time-course in ApoE3L mice. The initial perturbation of hepatic homeostasis by excess dietary fat triggers the stress response largely controlled by NF-κB and Akt regulators and manifested in activation of acute phase response, inflammation, immune response, hepatic regeneration-like response and lipotoxicity (day 1 to week 1). Upon prolonged high-fat feeding, liver fails to regain the basal state and consequently shifts to pathological state controlled by PPAR and SREBP regulators and characterized by hepatic lipid accumulation and adipogenic transformation, indicative of hepatic steatosis (late phase, week 8 to week 16). The flagship processes induced at the early and at the late phase are shown in boxes. The transition between the stressed and the pathological hepatic state may be controlled by trans-inhibitory interactions between NF-κB and PPARγ regulators, resulting in the tradeoff between inflammatory and steatotic transcription programs (mid phase, week 2 to week 4). On the systems level, the activation of steatotic program is followed by other metabolic syndrome associated pathologies such as obesity and whole-body insulin resistance.
Mentions: The dynamic functional landscape of the hepatic transcriptional adaptation to excess dietary fat during the 16-week time-course suggests a model in which sequential physiological changes underlie the transition from metabolic stress to metabolic syndrome, summarized in Figure 9. These results provide novel insight into the delicate cross-talk between inflammation and lipid metabolism in controlling the progression of metabolic disease development. It is important to note that the late repression of the hepatic NF-κB driven inflammatory/immune response may not seem in line with the established model of the obesity-associated inflammation, well studied in the adipose tissue [10], [67]. The previously shown association of inflammatory signaling pathways with obesity and hepatic steatosis is the most prominent feature observed in our data. Nevertheless, the assumption that, similar to the situation in adipose tissue, hepatic inflammation is secondary to hepatic steatosis is not supported by our findings [68], [69]. In fact, our results show that the temporal order of events contradicts this assumption, at least during the examined time frame and in our mouse model. Extending the duration of treatment and/or increasing amount of excess dietary fat would likely provoke transitions to further grades of severity in hepatic pathology such as hepatosteatitis, fibrosis, cirrhosis and hepatocellular carcinoma. To fully understand the complex relationship between inflammation and metabolic syndrome, information originating from different organs and at various time points needs to be considered on the systems level [69].

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