Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. In order to better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J× C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. QTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1 s and Socs3. We identified two overlapping loci for Xbp1 and Socs3 on Chr 1 (164.0 – 185.4 Mb and 174.4 – 190.5 Mb, respectively) and Chr 11 (41.1 – 73.1 Mb and 44.0 – 68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9 – 117.4 Mb). C57BL/6J-Chr 11A/J/NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1 s and Socs3 gene expression (p < 0.05), while C57BL/6J-Chr 1A/J/NaJ mice retained the C57BL/6 phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ≥ 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.

Corresponding author: Lammert, Frank

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