Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

Authors: KIM, MYUNGSUK - University Of California, Davis; HUDA, NAZMUL - University Of California, Davis; O'CONNOR, ANNA - University Of North Carolina; ALBRIGHT, JODY - University Of North Carolina; DURBIN-JOHNSON, BLYTHE - University Of California, Davis; Bennett, Brian

Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/26/2021
Publication Date: 5/13/2021
Citation: Kim, M., Huda, N., O'Connor, A., Albright, J., Durbin-Johnson, B., Bennett, B.J. 2021. Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross. Physiological Genomics. 53(5):173-192. https://doi.org/10.1152/physiolgenomics.00140.2020.
DOI: https://doi.org/10.1152/physiolgenomics.00140.2020

Interpretive Summary: Most of the experiments with mice so far have been performed in a small number of mouse strains and limited genetic variations, so they have not been genetically representative of the human. However, our study showed that by using mouse models with various genetic backgrounds, host genetics had a profound effect on gene expression in the liver depending on the diet. Differences of metabolic phenotypes between mouse strains motivates us to find comparable phenotypic variations across the human population. Understanding the liver transcriptome (set of all gene expression) in response to diet and genetic backgrounds will be important to highlight the potential of personalized nutrition and to understand interpersonal variability in disease risk.

Technical Abstract: Although mice are an important model in the study of metabolic syndrome, most studies on mice have been conducted with a small number of mouse strains and limited genetic variations. We investigated the diet- or strain-dependence of cardio-metabolic traits in eight Diversity Outbred founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Our liver transcriptomic analysis of eight mouse strains shows that diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in cardo-metabolic traits. We calculated a gene module composed of highly correlated transcripts that enriched the functional annotation and provided an accessible database of liver transcript profiles. To further investigate the association of hepatic gene modules with cardio-metabolic traits, Nox4, a key enzyme in the production of reactive oxygen species, which showed strong association with plasma TMAO and liver triglyceride, was identified as the highest expressed in the laboratory-like inbred strains (B6 and NZO) and the lowest expressed transcripts in the CAST strain. We found differences in the production of TMAO and liver triglyceride, which contributes to metabolic syndrome, depending on genetic backgrounds. Previous studies using only the B6 strain reported that the liver produces TMAO, the product of Fmo3, and that Fmo3 and TMAO have an association. Therefore, utilization of the eight founder strain was important for the discovery of strain-dependent differences for plasma TMAO and cardio-metabolic traits. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for cardio-metabolic traits.