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AMPK-beta1 Activation Induces Fetal Hemoglobin

ABSTRACT: Previous studies report that metformin triggers fetal hemoglobin (HbF) induction in human erythroid cells through indirect activation of the AMPK/FOXO3 pathway. Here we investigated the underlying mechanism of HbF induction by direct activation of AMPKβ1 in erythroid cells to understand their potential as safe medication for sickle cell disease (SCD). Single-cell RNA sequencing of human bone marrow cells determined that AMPKβ1 predominates in the erythroid lineage compared to AMPKβ2 and expression of AMPKβ1 is mostly restricted to this lineage. Novel selective AMPKβ1 activators greatly increased expression of HbF, activated markers of the noncanonical Nrf2 pathway (phosphorylated ULK1 and SQSTM1), and ultimately decreased sickling of SCD donor CD34+ cells under hypoxia. Confirmation of the noncanonical Nrf2 pathway in AMPKβ1 driven HbF induction was achieved by abolishing increased HbF using a potent and selective inhibitor for SQSTM1/Keap1 complex formation. Preclinical studies in Townes SCD mice treated with PF-06409577, a clinical candidate AMPKβ1 activator, confirmed increased HbF induction and non-canonical Nrf2 pathway activation in erythroid cells, associated with decreased reactive oxidative species in bone marrow and decreased chronic inflammation markers. Based on the narrow tissue expression of AMPKβ1, our study strongly supports AMPKβ1 activators as safe activators of Nrf2 driven HbF induction compared to direct inhibitors of ubiquitous Keap1. Activation of the AMPKβ1/Nrf2 noncanonical pathway may be a promising therapeutic approach for SCD patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223925 | GEO | 2025/05/21

REPOSITORIES: GEO

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Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.

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AMPK-beta1 Activation Induces Fetal Hemoglobin

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