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

Abstract

Mice have provided critical mechanistic understandings of clinical traits underlying Metabolic Syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-Oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.

Dexamethasone-induced muscle atrophy and bone loss in six genetically diverse collaborative cross founder strains demonstrates phenotypic variability by Rg3 treatment

“…The MGI and Wellcome Sanger Institute provide sequencing data of most of the inbred strains, including the eight CC founder strains. As a preliminary study, we analyzed the liver transcriptomes of eight CC founder strains fed a high-fat cholesterol diet and found that the NOX4, which is associated with hepatic triglyceride and plasma trimethylamine N-oxide level, may influence strain-specific responses to metabolic syndrome, and confirmed that Nox4 functional missense variants were caused by SNPs in the CAST and PWK strains [ 88 ]. In future studies, we will dissect muscle transcriptome to identify candidate genes and genetic variants regulating muscle atrophy that are differentially expressed by Rg3, are associated with muscle atrophy-traits, and carry missense variants of PWK SNPs.…”

Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

“…Briefly, samples were measured in duplicate using the EnzyChrom AF HDL and LDL/VLDL Assay kit (BioAssay Systems, Hayward, CA, USA). Liver triglyceride levels were determined using the Folch extraction method, as previously described in [ 59 ]. In brief, after performing necropsy the liver of the mouse was collected, frozen, and stored at -80°C for subsequent analysis.…”

Novel insights into metabolic‐associated steatotic liver disease preclinical models

“…in fat and carbohydrates, and have proven the significant impact of the genetic background in the liver (eg liver weight, hepatic TG accumulation, ALT, expression levels), metabolic (eg body weight, fat accumulation and distribution), symbiotic (eg microbiome) and behavioural traits (eg dietary habits). 146,147 The genetic background holds significant importance as the same diet could lead to a variety of phenotypes in these mice. For instance, Busnelli et al investigated the effect of both diet and genotype on the miRNome of mice with altered lipoprotein metabolism.…”

“…Working with well‐established genetically homogeneous strains is essential in order to maximize the reproducibility of results under our experimental conditions. Several studies have tested the effects on different inbred mouse strains fed the same diet, enriched in fat and carbohydrates, and have proven the significant impact of the genetic background in the liver (eg liver weight, hepatic TG accumulation, ALT, expression levels), metabolic (eg body weight, fat accumulation and distribution), symbiotic (eg microbiome) and behavioural traits (eg dietary habits) 146,147 …”