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Significant changes in hepatic transcriptome and circulating miRNAs are associated with diet-induced metabolic syndrome in apoE3L.CETP mice


Nasias, Dimitris; Evangelakos, Ioannis; Nidris, Vasilis; Vassou, Despoina; Tarasco, Erika; Lutz, Thomas A; Kardassis, Dimitris (2019). Significant changes in hepatic transcriptome and circulating miRNAs are associated with diet-induced metabolic syndrome in apoE3L.CETP mice. Journal of Cellular Physiology, 234(11):20485-20500.

Abstract

Long-term exposure to excess dietary fat leads to obesity and the metabolic syndrome (MetS). The purpose of the present study was to identify global changes in liver gene expression and circulating miRNAs in a humanized mouse model of diet-induced MetS. Male apoE3L.CETP mice received a high-fat diet (HFD) or a low-fat diet (LFD) for different time periods and the progression of MetS pathology was monitored. A separate group of mice was divided into responders (R) or nonresponders (NR) and received HFD for 16 weeks. We found that mice receiving the HFD developed manifestations of MetS and displayed an increasing number of differentially expressed transcripts at 4, 8, and 12 weeks compared with mice receiving the LFD. Significantly changed genes were functionally annotated to metabolic diseases and pathway analysis revealed the downregulation of genes in cholesterol and fatty acid biosynthesis and upregulation of genes related to lipid droplet formation, which was in line with the development of hepatic steatosis. In the serum of the apoE3L.CETP mice we identified three miRNAs that were upregulated specifically in the HFD group. We found that responder mice have a distinct gene signature that differentiates them from nonresponders. Comparison of the two diet intervention studies revealed a limited number of common differentially expressed genes but the expression of these common genes was affected in a similar way in both studies. In conclusion, the characteristic hepatic gene signatures and serum miRNAs identified in the present study provide novel insights to MetS pathology and could be exploited for diagnostic or therapeutic purposes.

Abstract

Long-term exposure to excess dietary fat leads to obesity and the metabolic syndrome (MetS). The purpose of the present study was to identify global changes in liver gene expression and circulating miRNAs in a humanized mouse model of diet-induced MetS. Male apoE3L.CETP mice received a high-fat diet (HFD) or a low-fat diet (LFD) for different time periods and the progression of MetS pathology was monitored. A separate group of mice was divided into responders (R) or nonresponders (NR) and received HFD for 16 weeks. We found that mice receiving the HFD developed manifestations of MetS and displayed an increasing number of differentially expressed transcripts at 4, 8, and 12 weeks compared with mice receiving the LFD. Significantly changed genes were functionally annotated to metabolic diseases and pathway analysis revealed the downregulation of genes in cholesterol and fatty acid biosynthesis and upregulation of genes related to lipid droplet formation, which was in line with the development of hepatic steatosis. In the serum of the apoE3L.CETP mice we identified three miRNAs that were upregulated specifically in the HFD group. We found that responder mice have a distinct gene signature that differentiates them from nonresponders. Comparison of the two diet intervention studies revealed a limited number of common differentially expressed genes but the expression of these common genes was affected in a similar way in both studies. In conclusion, the characteristic hepatic gene signatures and serum miRNAs identified in the present study provide novel insights to MetS pathology and could be exploited for diagnostic or therapeutic purposes.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:MetS; apoE3L.CETP mice; gene signatures; metabolic syndrome; microarrays; transcriptomics
Language:English
Date:November 2019
Deposited On:26 Aug 2019 16:01
Last Modified:25 Sep 2019 00:39
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0021-9541
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/jcp.28649
PubMed ID:31016757
Project Information:
  • : FunderFP7
  • : Grant ID305707
  • : Project TitleA systems biology approach to RESOLVE the molecular pathology of two hallmarks of patients with metabolic syndrome and its co-morbidities; hypertriglyceridemia and low HDL-cholesterol

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