Biology subjects
Publications and source records attributed to Akinborewa, O..
Withdrawal statementThe authors have withdrawn their manuscript because of an issue in genotype classification that requires correction and re-analysis. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene encoding the GR, rs6190, associated with increased cholesterol in women according to UK Biobank and All Of Us datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptors respectively. In mice, the SNP was sufficient to elevate circulating cholesterol across all lipoprotein fractions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo liver knockdown of Pcsk9 and Bhlhe40. Also, corticosterone and tes-tosterone were protective against the mutant GR program in cholesterol and atherosclerosis in male mice, while the SNP effect was additive to estrogen loss in females. Remarkably, we found that the mutant GR program was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/625727v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@158e895org.highwire.dtl.DTLVardef@d9a2corg.highwire.dtl.DTLVardef@104e6bcorg.highwire.dtl.DTLVardef@c87160_HPS_FORMAT_FIGEXP M_FIG C_FIG
The genetic determinants of the glucocorticoid receptor (GR) metabolic action remain largely unelucidated. This is a compelling gap in knowledge for the GR single nucleotide polymorphism (SNP) rs6190 (p.R23K), which has been associated in humans with enhanced metabolic health but whose mechanism of action remains completely unknown. We generated transgenic knock-in mice genocopying this polymorphism to elucidate how the mutant GR impacts metabolism. Compared to non-mutant littermates, mutant mice showed increased insulin sensitivity on regular chow and high-fat diet, blunting the diet-induced adverse effects on adiposity and exercise intolerance. Overlay of RNA-seq and ChIP-seq profiling in skeletal muscle revealed increased transactivation of Foxc1 and Arid5A genes by the mutant GR. Using myotropic adeno-associated viruses for in vivo overexpression or knockdown in muscle, we found that Foxc1 was required and sufficient for normal expression levels of insulin response pathway genes Insr and Irs1, promoting muscle insulin sensitivity. In parallel, Arid5a was required and sufficient to transcriptionally repress the lipid uptake genes C 36 and Fabp4, reducing muscle triacylglycerol accumulation. Moreover, the Foxc1 and Arid5a programs in muscle were divergently changed by glucocorticoid regimens with opposite metabolic outcomes in muscle. Finally, we found a direct human relevance for our mechanism of SNP action in the UK Biobank and All of Us datasets, where the rs6190 SNP correlated with pro-metabolic changes in BMI, lean mass, strength and glucose control according to zygosity. Collectively, our study leveraged a human nuclear receptor coding variant to unveil novel epigenetic regulators of muscle metabolism. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/586997v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1af900borg.highwire.dtl.DTLVardef@119dcaforg.highwire.dtl.DTLVardef@e78baeorg.highwire.dtl.DTLVardef@1835427_HPS_FORMAT_FIGEXP M_FIG C_FIG