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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) 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.
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miR-191, miR-221-5p, miR-222, miR-224, miR-342-5p, miR-363-5p, miR-483, miR-520d, miR-609, miR-765, miR-3165, and miR-1908-5p inhibit expression of PCSK9, increasing LDLR.
“miR-191, miR-221-5p, miR-222, miR-224, miR-342-5p, miR-363-5p, miR-483, miR-520d, miR-609, miR-765, miR-3165, miR-1908-5p Inhibit expression of PCSK9 ↑ [50-55]”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [55]
In ‘Identification of Potential Target Genes of miR-1908-5p’ (page unavailable), the paper reports that total LDLR protein remained unchanged after miR-1908-5p treatment, contrary to the claimed increase in LDLR. Its conclusion instead attributes improved LDLR function to reduced TGFB1, BMP1, and LDLR cleavage; it does not report PCSK9 inhibition or test the other listed miRNAs. (LLM, conf=0.83)
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Experimental — accuracy not yet measuredGenetically determined expression of miR-1908-5p governs LDL uptake.
“Therefore, genetically determined expression of miR-1908-5p governs LDL uptake [55].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [55]
The Introduction and cell experiments link the rs174561-C allele to higher miR-1908-5p expression and show that altering miR-1908-5p changes LDLR cleavage. But the Discussion explicitly says LDL binding and uptake were not directly assessed; enhanced uptake is inferred from the LDLR findings. It also describes the miRNA’s effect as fine-tuning rather than a major regulatory role, making “governs” too strong. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCarriers of the rs-174561-C variant in the miR-1908-5p locus have decreased expression of TGF-β, which is a key driver of BMP1.
“It is intriguing that carriers of the rs-174561-C variant in the miR-1908-5p locus (discussed above in miRNA section) have decreased expression of TGF-β, which is a key driver of BMP1 [55].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [55]
The section “rs174561-C Confers Higher Expression of miR-1908-5p Versus rs174561-T” reports higher miR-1908-5p expression with the C allele in transfected HuH-7 cells. “TGF-β Signaling Regulates BMP1 Expression and LDLR Cleavage” reports that miR-1908-5p mimic treatment reduces TGFB1 expression and signaling, and that TGF-β signaling increases BMP1 expression. The paper does not report measuring decreased TGF-β expression in people carrying the C allele; that part of the claim presents a proposed cellular mechanism as a finding in carriers. Page numbers were not supplied for these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmiR-224 and miR-520d inhibit expression of IDOL, increasing LDLR.
“miR224, miR520d Inhibit expression of IDOL ↑ [50-55]”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [55]
The ‘Identification of Potential Target Genes of miR-1908-5p’ section discusses miR-1908-5p and LDLR cleavage, not miR-224 or miR-520d. Searches for those miRNAs and for IDOL found no passage in our copy addressing whether they inhibit IDOL or increase LDLR. (LLM, conf=0.75)
Experimental — accuracy not yet measuredCarriers of the rs-174561-C variant in the miR-1908-5p locus have increased expression of miR-1908-5p and consequently lower circulating LDL.
“Carriers of the rs-174561-C variant in the miR-1908-5p locus have increased expression of miR-1908-5p and consequently lower circulating LDL [55].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [55]
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Cited by
Sorted by citations
The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 17
Metadata
- Authors
- Beehler, K., Nikpay, M., Lau, P., Dang, A.-T., Lagace, T. A., Soubeyrand, S., & McPherson, R.
- Affiliations
- Atherogenomics Laboratory (K.B., M.N., P.L., A.-T.D., S.S., R.M.), University of Ottawa Heart Institute, Canada.
- Lipoprotein Receptor Biology Laboratory (T.A.L.), University of Ottawa Heart Institute, Canada.
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2021-08
- Volume
- 41
- Issue
- 8
- Pages
- 2252-2262
- ISSN
- 1079-5642
- 1524-4636
- Cited by
- 9
- References
- 0
- Language
- en
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