Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

Abstract

BackgroundFibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, small heterodimer partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis.ResultsThe overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels.ConclusionThis study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0835-6) contains supplementary material, which is available to authorized users.

Farnesoid X receptor signaling activates the hepatic X‐box binding protein 1 pathway in vitro and in mice

“…Recent studies have shown that IRE1α signaling can be regulated independent of ER stress through protein interactions . Although SHP is generally considered as a transcriptional repressor, it has now been shown to interact with other proteins and regulate functions throughout the cell . We demonstrate that SHP and IRE1α can interact and this interaction may be responsible for the increased p‐IRE1α and XBP1s expression that occurs with FXR agonist stimulation.…”

“…(23) Although SHP is generally considered as a transcriptional repressor, it has now been shown to interact with other proteins and regulate functions throughout the cell. (27,(41)(42)(43) We demonstrate that SHP and IRE1a can interact and this interaction may be responsible for the increased p-IRE1a and XBP1s expression that occurs with FXR agonist stimulation. FXR shares many common target genes with LRH-1.…”

No Gut No Gain! Enteral Bile Acid Treatment Preserves Gut Growth but Not Parenteral Nutrition–Associated Liver Injury in a Novel Extensive Short Bowel Animal Model

“…No statistical differences in hepatic FGF19 ( P = .86), hepatic FGFR4 ( P = .53), a receptor for FGF19, hepatic CyP7A1 ( P = .61), or hepatic FXR ( P = .75) were noted between the 2 groups (Figure ). In addition, no statistical differences in known CDCA‐modulated hepatic receptors, small heterodimer partner (SHP), constitutive androstane receptor (CAR), organic solute steroid transporter (OSTα), multidrug‐associated protein (MRP), or peroxisome proliferator‐activated receptor (PPAR) were noted between the groups.…”

Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice

“…Direct fatty acid metabolism genes involved in fatty acid synthesis, desaturation, and elongation were separately analyzed and visualized by Gene Cluster 3.0 (http://bonsai.hgc.jp/-mdehoon/software/cluster/) and Java Treeview program (http://jtreeview.sourceforge.net/). For chromatin immunoprecipitation (ChIP) sequencing (seq) results, FXR (University of California Santa Cruz Genome Browser Custom Tracks, https://genome.ucsc.edu/goldenPath/customTracks/custTracks.html) and SHP (GSE74913, Gene Expression Omnibus data set) binding were visualized using Integrative Genomics Viewer software (Broad Institute).…”