Liver-specific matrin-3 knockout alters the hepatic transcriptome of high-fat diet-fed mice [RNA-seq]

Matrin-3 is an RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor. Matrin-3 expression was induced in the steatotic livers of mice and humans. Liver-specific matrin-3 knockout (LKO) exacerbated high-fat diet (HFD)-induced steatosis, acute phase response, and inflammation in the liver of mice. Bulk RNA-seq and bioinformatics analysis identified 1,333 and 239 differentially expressed genes (fold change > 1.5 & Padj < 0.05), respectively in the livers of female and male matrin-3 LKO mice. Gene Set Enrichment Analysis revealed that the top most enriched Gene Ontology Biological Process was the “Xenobiotic metabolic process” in female matrin-3 floxed mice that is downregulated. The top two enriched biological processes are “Acute inflammatory response” and “Acute phase response” in the liver of female LKO mice that are upregulated. Several GO terms related to lipid metabolism and xenobiotic metabolism were enriched in the livers of male mice. Real-time qPCR revealed that the expression of many genes involved in xenobiotic metabolism was reduced in the liver of female LKO mice and to a lesser extent in the liver of male LKO mice, while the expression of acute-phase response genes was induced in the liver of female but not male LKO mice. Our data demonstrated that liver-specific matrin-3 deficiency re-programs the hepatic transcriptome enriched for xenobiotic metabolism pathway, acute-phase and inflammatory response signaling in the liver of HFD-fed mice. Matrin-3 floxed mice were bred with Albumin-Cre mice (The Jackson Laboratory, #003574) to produce liver-specific matrin-3 knockout mice (LKO). Mice were housed on a normal 12/12 light-dark cycle. Mice had ad libitum access to a normal chow diet (Envigo, cat# 2016) and water, or a HFD with 60 kcal% fat (Research Diets, D12492) and water. Male and female matrin-3 floxed mice and littermate LKO mice were fed a HFD at 7 weeks of age for 16 weeks. Sixteen weeks post-HFD, mice were fasted for 12 hours for euthanasia and tissue collection. Total RNAs were extracted from mouse tissues after homogenization using TRIzol Reagent (Thermo Fisher, 15596026) according to the manufacturer’s instructions. For RNA sequencing by Novogene, total RNA quality was examined using Agilent 2100 Bioanalyzer. The RNA Integrity Number of each RNA sample is above 8.5. A total amount of 1 µg RNA per sample was used for library construction.