OXR1A deficient male mouse displays fatty liver associated with impaired transcription regulation of hormone response and lipid metabolism

Purpose: The Oxidation Resistance gene 1 (Oxr1) protects cells against oxidative stress and involves in transcription regulation. Here we generated the brain specific isoform A knockout mice (Oxr1A-/-). Unexpectedly, the male mice developed fatty liver with large number of lipid-droplets at 12 months. To understand the mechanism of the phenotype, we investigated the transcriptome profile of Oxr1A-/- mice liver both in male and female by RNA sequencing and compared to wild type. Methods: The OXR1A knockout mice were generated by gene trap approach to targeted on OXR1 isoform A specific exons. Total RNA was pooled from triplicate liver samples of male and female mice at 12 months old in knockout and control groups and performed RNA sequencing on an Illumina HiSeq 2500 platform. The sequence reads that passed quality filters were analyzed at gene level. The GOseq program was used to generate gene ontology (GO) annotation of differentially expressed genes (DEGs). The pathway enrichments were identified by KEGG Pathway Enrichment Analysis. qRT–PCR validation was performed using SYBR Green assays. Results: We identified total 724 differentially expressed genes (DEGs) between OXR1A-/- and wild type in male mice, while only 169 DEGs were identified in female. For the male, OG analysis revealed that a subset of 22 DEGs involved in fatty acid metabolism and transport, while 24 DEGs involved in hormone response and 164 DEGs involved in immune response. Conclusions: Enrichment of differentially expressed genes (DEGs) in the liver of male Oxr1A-/- mice associated with hormone response, fatty liver metabolism and immune response. The differential expression profiles were generated by comparsion in the liver tissues between wild type and OXR1A difficent mice.