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

Marijana Radonjic*, Jorn R. de Haan, Marjan J. van Erk, Ko Willems van Dijk, Sjoerd A.A. van den Berg, Philip J. de Groot, Michael Müller, Ben van Ommen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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-κB, NEMO, Akt, PPARγ 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-κB and PPARγ 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.

Original languageEnglish
Article numbere6646
JournalPLoS ONE
Volume4
Issue number8
DOIs
Publication statusPublished - 14 Aug 2009
Externally publishedYes

Bibliographical note

Funding:
This work is financially supported by Top Institute Food and Nutrition, The Netherlands (Nutrigenomics Consortium, project A-006) and the resident
institutes of the authors. All authors are member of the Nutrigenomics consortium (www.nutrigenomicsconsortium.nl) and European Nutrigenomics Organisation
(www.nugo.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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