Identification of coinciding quantitative trait loci for the hepatic expression of SOCS3 and XBP-1 s during toxic and non-alcoholic fatty liver disease

Toxic and non-alcoholic fatty liver diseases are multifactorial (polygenic) disorders. A valuable tool to identify disease associated genetic loci is Quantitative Trait Locus (QTL) mapping, i.e. genome-wide linkage analysis of genetic and phenotypic variation in experimental crosses. Here we employ QTL mapping to analyze the regulation of two previously identified mediators of non-alcoholic fatty liver disease (NAFLD), the inflammatory mediator SOCS3 and the unfolded protein response regulator XBP-1 s. In the first study, F2 intercross progeny of the inbred mouse lines A/J and C57BL/6J were fed a high-fat/high caloric (HFHC) diet for eight weeks and then used to identify QTLs determining the hepatic expression of Socs3 and Xbp1 s (eQTLs). Overlapping eQTLs for Xbp1 s and Socs3 were identified on chromosomes (chr) 1 at (181.5 Mb) and 11 (56.2 and 58.4 MB), and a Socs3 QTL was localized on chr 12 (113.4 Mb). Microarray analysis identified differentially-expressed candidate genes within these QTLs. We then phenotyped 33 BXD recombinant inbred lines (Andreux et al. Cell 2012) after induction of hepatic fibrosis with the hepatotoxin CCl₄ (1.4 mg/kg/week for 6 weeks). The transcriptome of each BXD line after CCl₄ challenge was determined with Affymetrix Mouse Gene 1.0 ST microarrays. Using gene expression values as quantitative traits, we searched for coinciding regulatory loci within the Socs3 and Xbps1 QTLs on chr 1, 11, and 12. After CCl₄ challenge, we mapped four eQTLs on chr 1 at 193.7 Mb, chr 4 at 63.4 Mb, chr 11 at 47.9 Mb, and chr 15 at 103 Mb. Among these, we found loci overlapping with the eQTLs that determine Socs3 and Xbps1 expression on the HFHC diet. Furthermore, we identified several cis-regulated genes from within these QTLs that were also identified to be differentially regulated after the HFHC challenge. In summary, the complementary genetic studies identify co-localizing regulatory loci for Socs3 and Xbps1 expression after liver injury induced by either dietary (high-fat) or toxic (CCl₄) challenge. These results propose further investigation of the Socs3 and Xbps1 QTLs and their roles during chronic liver injury, as they might represent critical mediators in the pathobiology of steatohepatitis.