A Common Polymorphism in the FADS1 Locus Links miR1908 to Low-Density Lipoprotein Cholesterol Through BMP1

Abstract

Objective: Leveraging microRNA-Seq data and the 1000 Genomes imputed genotypes, we identified rs174561 as a strong microRNA quantitative trait loci for circulating microRNA-1908-5p with higher miR-1908-5p and reduced LDL (low-density lipoprotein)-cholesterol, fasting glucose and A1c concentrations in carriers of the rs-174561-C allele. Here, we have investigated the molecular mechanism(s) linking miR-1908-5p to LDL-C concentrations. Approach and Results: Transfection experiments demonstrate that the presence of the C allele significantly increases miR-1908-5p abundance relative to the T allele. LDLR mRNA and low-density lipoprotein receptor (LDLR) total protein were unchanged in response to differential miR-1908-5p expression. However, the ratio of the cleaved to full-length form of LDLR decreased with miR-1908-5p mimic and increased with miR-1908-5p inhibitor treatment. BMP1 (bone morphogenetic protein 1) is a protease responsible for LDLR cleavage, and we show that miR-1908-5p mimic reduces BMP1 mRNA. Using a reporter array, we identified the TGF-β (transforming growth factor-beta 1) signaling pathway activity to be reduced by miR-1908-5p mimic treatment, and this was associated with reduced TGFB1 expression. TGF-β signaling increases BMP1, and we further demonstrate that the effect of miR-1908-5p on LDLR cleavage is abolished by exogenous TGF-β treatment. Conclusions: These findings uncover a mechanism whereby miR-1908-5p reduces TGFB1 abundance resulting in lower expression of BMP1 , ultimately leading to reduced LDLR cleavage. Cleavage of the mature LDLR is known to reduce cell surface affinity for LDL, thereby linking miR-1908-5p to lower circulating LDL-cholesterol levels.

miR1908-5p regulates energy homeostasis in hepatocyte models

“…Interestingly, both ORA and IPA implicate TGFB signaling (GO:0007179 and “TGF-β Signaling”) in both primary hepatocytes and HuH-7 cells (Tables S4 and S8 ). These findings are consistent with our prior work demonstrating reduced TGFB abundance in response to mimic treatment 4 . Uniquely, GSEA identified increased mitochondria function (TCA cycle, respiratory electron cycle etc.).…”

“…6 , 8 ). A similar pattern was observed in our prior characterization of TGFB in response to miR1908-5p inhibitor 4 . The lack of statistical power may explain why transcriptome analyses of mimic- and inhibitor-treated cells are incoherent: introduction of exogenously sourced miR1908-5p mimic leads to the silencing of miR1908-5p targets that are basally only weakly impacted, perhaps because of their higher basal expression relative to endogenous miR1908-5p.…”

“…By 2-Sample Mendelian Randomization analysis, we demonstrated these to be causal associations 1 . Mechanisms linking LDL-C to miR1908-5p were recently clarified when we demonstrated that miR1908-5p promotes LDL receptor function via suppression of Transforming Growth Factor beta and Bone Morphogenic Protein 1 4 . Here we have explored the relationship between miR1908-5p and glycemic variables.…”

miR-1908 Dysregulation in Human Cancers

“…As shown in Figure 5 , miR-1908-5p does not affect the expression of low-density lipoprotein receptor (LDLR) but can reduce the expression of bone morphogenetic protein 1 (BMP1) by targeting TGF-β1. Down-regulation of BMP1 expression can increase the stability of LDLR, which in turn promotes the absorption of LDL-C by liver cells, thereby reducing circulating low-density lipoprotein-cholesterol (LDL-C) levels ( 11 ), and ultimately reducing the risk of cardiovascular disease ( 57 ).…”

“…Although miR-1908 is a relatively newly discovered miRNA, more and more molecular mechanisms of miR-1908 have been discovered recently ( 11 , 12 ). miR-1908 plays an important role in many human diseases, especially cancer, and there is no systematic description of miR-1908.…”