ArticleHuman molecular genetics2014
HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 63 citations in OpenAlex.
- Emerging roles of the metabolic regulator 3-hydroxy-3-methylglutaryl coenzyme-CoA reductase in human cancers: From biology to therapeutics.Genes & diseases · 2026Review
- Alternative Splicing Regulation in Metabolic Disorders.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Review
- Multi-omics association study of DNA methylation and gene expression levels and diagnoses of cardiovascular diseases in Danish Twins.Clinical epigenetics · 2024Article
- Effect of hypercholesterolemia on circulating and cardiomyocyte-derived extracellular vesicles.Scientific reports · 2024Article
- Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis.Nature communications · 2023Article
- hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target.Frontiers in pharmacology · 2022Review
- Body Complexion and Circulating Lipids in the Risk of TDP-43 Related Disorders.Frontiers in aging neuroscience · 2022Article
- Review
- A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial HypercholesterolemiaIranian biomedical journal · 2021Article
- Identifying genetic modulators of statin response using subject-derived lymphoblastoid cell lines.Pharmacogenomics · 2021Review
- Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis.Scientific reports · 2021Article
- Lipid metabolism and cancer.The Journal of experimental medicine · 2021Review
- Article
- Personalised medicine in hypercholesterolaemia: the role of pharmacogenetics in statin therapy.Annals of medicine · 2020Review
- Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- eXplainable Artificial Intelligence (XAI) for the identification of biologically relevant gene expression patterns in longitudinal human studies, insights from obesity research.PLoS computational biology · 2020Article
- Children Are Not Small Adults: Specific Findings in Statin Exposure and Response in a Growing Population.Clinical pharmacology and therapeutics · 2019Article
- Weighted gene co-expression network analysis to explain the relationship between plasma total carotenoids and lipid profile.Genes & nutrition · 2019Article
- The Splicing Factor hnRNPA1 Regulates Alternate Splicing of the MYLK Gene.American journal of respiratory cell and molecular biology · 2018Article
- Relationship between Lipid Phenotypes, Overweight, Lipid Lowering Drug Response and KIF6 and HMG-CoA Genotypes in a Subset of the Brisighella Heart Study Population.International journal of molecular sciences · 2017Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) encodes the rate-limiting enzyme in the cholesterol biosynthesis pathway and is inhibited by statins, a class of cholesterol-lowering drugs. Expression of an alternatively spliced HMGCR transcript lacking exon 13, HMGCR13(-), has been implicated in the variation of plasma LDL-cholesterol (LDL-C) and is the single most informative molecular marker of LDL-C response to statins. Given the physiological importance of this transcript, our goal was to identify molecules that regulate HMGCR alternative splicing. We recently reported gene expression changes in 480 lymphoblastoid cell lines (LCLs) after in vitro simvastatin treatment, and identified a number of statin-responsive genes involved in mRNA splicing. Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) was chosen for follow-up since rs3846662, an HMGCR SNP that regulates exon 13 skipping, was predicted to alter an HNRNPA1 binding motif. Here, we not only demonstrate that rs3846662 modulates HNRNPA1 binding, but also that sterol depletion of human hepatoma cell lines reduced HNRNPA1 mRNA levels, an effect that was reversed with sterol add-back. Overexpression of HNRNPA1 increased the ratio of HMGCR13(-) to total HMGCR transcripts by both directly increasing exon 13 skipping in an allele-related manner and specifically stabilizing the HMGCR13(-) transcript. Importantly, HNRNPA1 overexpression also diminished HMGCR enzyme activity, enhanced LDL-C uptake and increased cellular apolipoprotein B (APOB). rs1920045, an SNP associated with HNRNPA1 exon 8 alternative splicing, was also associated with smaller statin-induced reduction in total cholesterol from two independent clinical trials. These results suggest that HNRNPA1 plays a role in the variation of cardiovascular disease risk and statin response.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.