[en] Plasma lipids are modulated by gene variants and many environmental factors, including diet-associated weight gain. However, understanding how these factors jointly interact to influence molecular networks that regulate plasma lipid levels is limited. Here, we took advantage of the BXD recombinant inbred family of mice to query weight gain as an environmental stressor on plasma lipids. Coexpression networks were examined in both nonobese and obese livers, and a network was identified that specifically responded to the obesogenic diet. This obesity-associated module was significantly associated with plasma lipid levels and enriched with genes known to have functions related to inflammation and lipid homeostasis. We identified key drivers of the module, including Cidec, Cidea, Pparg, Cd36, and Apoa4. The Pparg emerged as a potential master regulator of the module as it can directly target 19 of the top 30 hub genes. Importantly, activation of this module is causally linked to lipid metabolism in humans, as illustrated by correlation analysis and inverse-variance weighed Mendelian randomization. Our findings provide novel insights into gene-by-environment interactions for plasma lipid metabolism that may ultimately contribute to new biomarkers, better diagnostics, and improved approaches to prevent or treat dyslipidemia in patients.
Disciplines :
Genetics & genetic processes
Author, co-author :
Xu, Fuyi; School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Ziebarth, Jesse D ; Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Goeminne, Ludger Je; Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, Lausanne, Switzerland
Gao, Jun ; Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
WILLIAMS, Evan ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Gene Expression and Metabolism
Quarles, Leigh D; Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Makowski, Liza; Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Cui, Yan ; Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Williams, Robert W; Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
Auwerx, Johan; Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, Lausanne, Switzerland. Electronic address: johan.auwerx@epfl.ch
Lu, Lu; Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA. Electronic address: lulu@uthsc.edu
External co-authors :
yes
Language :
English
Title :
Gene network based analysis identifies a coexpression module involved in regulating plasma lipids with high-fat diet response.
This work was supported by grants from the École Polytechnique Fédérale de Lausanne (EPFL), the European Research Council (AdG-787702), the Swiss National Science Foundation (SNSF 31003A-179435), and the NIH R01AG043930 to JA; NIH R01DK120567 to LL and LDQ; CITG fund from UTHSC to RWW; American Heart Association 19TPA34910232 and R01CA253329, to LM; R01CA262112 to LM, RWW, and LL; the Swiss Government Excellence Scholarship (FCS ESKAS-Nr. 2019.0009) to LJEG; the Binzhou Medical University Research Start-up Fund (50012305190) to FX. We also thank Dr. Robert Read for his histologic work of livers.This work was supported by grants from the École Polytechnique Fédérale de Lausanne (EPFL) , the European Research Council ( AdG-787702 ), the Swiss National Science Foundation ( SNSF 31003A-179435 ), and the NIH R01AG043930 to JA; NIH R01DK120567 to LL and LDQ; CITG fund from UTHSC to RWW; American Heart Association 19TPA34910232 and R01CA253329 , to LM; R01CA262112 to LM, RWW, and LL; the Swiss Government Excellence Scholarship ( FCS ESKAS-Nr. 2019.0009 ) to LJEG; the Binzhou Medical University Research Start-up Fund ( 50012305190 ) to FX. We also thank Dr. Robert Read for his histologic work of livers.
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