Biology subjects

Iribarren, C.

Publications and source records attributed to Iribarren, C..

3 recordsLinked to original sources

bioRxiv2025

MIR192 Upregulates GLP-1 Receptor and Improves Statin-Induced Impairment of Insulin Secretion

Statins are a commonly prescribed cholesterol lowering drug class that can increase the risk of new-onset diabetes (NOD). To investigate the molecular mechanisms underlying this effect, we generated human induced pluripotent stem cells (iPSCs) from individuals identified from electronic health records of Kaiser Permanente of Northern California who were susceptible to developing NOD after statin initiation or controls who maintained stable fasting glucose on statin treatment. RNA-seq analysis of iPSCs incubated with atorvastatin, simvastatin or mock buffer for 24 hours identified the long non-coding RNA MIR194-2HG as a top candidate gene. Statin-induced increases in its expression were observed in NOD resistant controls, while statin-induced reductions occurred in NOD susceptible cases. MIR194-2HG encompasses two microRNA genes: MIR192 and MIR194-2. The mature microRNA miR-192-5p, derived from the 5 arm of MIR192, was predicted to bind the 3UTR of the glucagon like peptide 1 (GLP-1) receptor (GLP1R) transcript. Transfection of a rat insulinoma cell line INS-1 with a miR-192-5p mimic increased Glp1r transcript (1.41-fold) and protein (1.51-fold) levels compared to a scrambled control. Using a luciferase reporter containing the human GLP1R 3UTR, miR-192-5p overexpression similarly increased luciferase signal (1.44-fold). The miR-192-5p mimic enhanced glucose stimulated insulin secretion (GSIS) in response to GLP1R agonists (1.64-1.81-fold) and rescued simvastatin-induced GSIS impairment in INS-1 cells. Wild-type mice treated with miR-192 AAV8 had improved glucose sensitivity. Islets isolated from these mice exhibited enhanced GLP-1 potentiated GSIS during perifusion ex vivo. These effects were absent in the DIRKO (Glp1r/Gipr double knockout) mouse islets, consistent with the idea that miR-192 promotes GLP-1 mediated GSIS through GLP1R. These findings implicate MIR192 in statin-induced impairment of GSIS by modulating GLP1R, potentially contributing to the susceptibility to NOD in statin users.

cell biology↗

bioRxiv2022

X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. We determined that female mice are more susceptible than males to glucose intolerance, fasting hyperglycemia, and muscle weakness after short-term statin treatment. Lipidomic, transcriptomic, and biochemical analyses identified reduced docosahexaenoic acid (DHA) levels, and impaired redox tone and mitochondrial respiration specifically in statin-treated female mice. Statin adverse effects could be prevented in females by complementation with a source of DHA. Statin adverse effects segregated with XX chromosome complement, and specifically dosage of the Kdm5c gene, which regulates fatty acid gene expression and has differential expression levels in females and males. In humans, we found that women experience more severe reductions than men in DHA levels after short-term statin administration, and that DHA reduction was correlated with increases in fasting glucose levels. Furthermore, induced pluripotent stem cells derived from women, but not men, who developed NOD exhibited impaired mitochondrial function when treated with statin. Overall, our studies identify biochemical mechanisms, biomarkers, and a genetic risk factor for susceptibility to statin adverse effects, and point to DHA supplementation as a preventive co-therapy.

physiology↗

bioRxiv2019

Analysis of putative cis-regulatory elements regulating blood pressure variation

Hundreds of loci have been associated with blood pressure traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in [~]100,000 Genetic Epidemiology Research on Aging (GERA) study participants. In the present study, we subsequently focused on determining putative regulatory regions for these and other tissues of relevance to blood pressure, to both fine-map these loci by pinpointing genes and variants of functional interest within them, and to identify any novel genes.\n\nWe constructed maps of putative cis-regulatory elements using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Sequence variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. In order to identify genes of interest, we aggregate these variants in these putative cis-regulatory elements within 50Kb of the start or end of genes considered as \"expressed\" in these tissues or cell types using publicly available gene expression data, and use the deltaSVM scores as weights in the well-known group-wise sequence kernel association test (SKAT). We test for association with both blood pressure traits as well as expression within these tissues or cell types of interest, and identify several genes, including MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B, and PPCDC. Although our study centers on blood pressure traits, we additionally examined two known genes, SCN5A and NOS1AP involved in the cardiac trait QT interval, in the Atherosclerosis Risk in Communities Study (ARIC), as a positive control, and observed an expected heart-specific effect. Thus, our method may be used to identify variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.\n\nAuthor SummarySequence change in genes (\"variants\") are linked to the presence and severity of different traits or diseases. However, as genes may be expressed in different tissues and at different times and degrees, using this information is expected to more accurately identify genes of interest. Variants within the genes are essential, but also in the sequences (\"regulatory elements\") that control the genes expression in different tissues or cell types. In this study, we aim to use this information about expression and variants potentially involved in gene expression regulation to better pinpoint genes and variants in regulatory elements of interest for blood pressure regulation. We do so by taking advantage of such data that are publicly available, and use methods to combine information about variants in aggregate within a genes putative regulatory elements in tissues thought to be relevant for blood pressure, and identify several genes, meant to enable experimental follow-up.

genomics↗