Biology subjects

Fan, W.

Publications and source records attributed to Fan, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

EGF/STAT1 signals to maintain ECM1 expression in hepatic homeostasis are disrupted by IFNγ/NRF2 in chronic liver disease

In healthy livers, extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-{beta} (LTGF-{beta}) quiescent. Upon hepatocyte damage, ECM1 is downregulated, facilitating LTGF-{beta} activation and fibrogenesis. However, little is known about how hepatic ECM1 is regulated. Here we found in healthy hepatocytes, EGF/EGFR signaling sustains ECM1 expression through phosphorylating STAT1 at S727, enhancing its binding to the ECM1 promoter and boosting gene transcription. During liver inflammation, accumulating IFN{gamma} disrupts this process by downregulating EGFR and inhibiting EGF/EGFR/STAT1-mediated ECM1 promoter binding. Mechanistically, IFN{gamma}-induced STAT1 phosphorylation at Y701 impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFN{gamma} induces NRF2 nuclear translocation, which repressively binds to the ECM1 promoter, further reducing its expression. These findings were confirmed in several chronic liver disease (CLD) mouse models. Moreover, AAV8-ECM1 significantly attenuates liver fibrosis and injuries in Western diet (WD)-fed mice. Notably, in patients with CLD, ECM1 levels align with EGFR expression, while NRF2 and LTGF-{beta} activation show a negative correlation with both.

cell biology↗

bioRxiv2024

Unraveling principles of thermodynamics for genome-scale metabolic networks using graph neural networks

The fundamental laws of thermodynamics determine the feasibility of all natural processes including metabolism. Although several algorithms have been developed to predict the most important thermodynamic parameter, the standard Gibbs free energy, for metabolic reactions and metabolites, their application to genome-scale metabolic networks (GEMs) with thousands of metabolites and reactions is still limited. Here, we develop a graph neural network (GNN)- based model dGbyG for predicting Gibbs energy for metabolites and metabolic reactions which outperforms all existing methods in accuracy, versatility, robustness, and generalization ability. By applying dGbyG to the human GEM, Recon3D, we identify a critical subset of reactions with substantial negative values of the standard Gibbs free energy change, which we name thermodynamic driver reactions. These reactions exhibit distinctive network topological characteristics akin to driver nodes defined in control theory and remarkable heterogeneity in enzyme abundance, implying evolutionary constraints on the selection of thermodynamic parameters of metabolic networks. We also develop a thermodynamics-based flux balance analysis (TFBA) approach to integrate reaction thermodynamics with GEMs to curate these models. Our work not only transcends the augmentation of accessible thermodynamic data to facilitate an enriched understanding of metabolism, but also enables refinement of metabolic reconstructions from a thermodynamic perspective, thereby underscoring the critical role of thermodynamics in the accurate modeling of biological systems.

systems biology↗

bioRxiv2023

Extracellular Matrix Protein 1 Attenuates Hepatic Fibrosis by Inhibiting TSP-, ADAMTS-, and MMP-Mediated Latent TGF-β1 Activation

ObjectiveExtracellular Matrix Protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-{beta}1 (TGF-{beta}1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-{beta}1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-{beta}1 bioavailability and its impact on CLD progression. DesignRNAseq was performed to analyze hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue, and computer simulations. ResultsExpression of LTGF-{beta}1 activators, including thrombospondins (TSPs), ADAMTS proteases, and matrix metalloproteinases (MMPs) increased along with pro-fibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented TSP-1-, ADAMTS1-, and MMP-2/9-mediated LTGF-{beta}1 activation. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-{beta}1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences, and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-{beta}1 activation, while KTFR treatment reversed Ecm1-KO- and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-{beta}1 activation. And these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. ConclusionOur findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-{beta}1 activation, suggesting ECM1 or its representative peptide as potential anti-fibrotic therapies in CLD. What is already known on this topic?[tpltrtarr] ECM1 expression is negatively correlated with CLD progression. [tpltrtarr]ECM1 maintains liver homeostasis by keeping TGF-{beta}1 latency. What this study adds?[tpltrtarr] ECM1 inhibits LTGF-{beta}1 activation through interfering with key activators, including TSP-1, ADAMTS1, MMP-2, and MMP-9. [tpltrtarr]ECM1 interacts with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid motifs, and suppresses MMP-2/9 proteolytic activity. [tpltrtarr]In vivo, ECM1 overexpression mitigates KRFK peptide-induced LTGF-{beta}1 activation, while KTFR peptide rescues Ecm1-KO- and Fxr-KO-induced liver injury. [tpltrtarr]ECM1 expression inversely correlates with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-{beta}1 activation in CLD patients. How might this study affect research, practice or policy?[tpltrtarr] Considering severe adverse effects associated with anti-fibrotic treatments utilizing TGF-{beta}1 receptor inhibitors, our findings indicate that restoration of ECM1 expression or phenocopying peptides might represent a novel and safe route to urgently needed anti-fibrotic therapies in CLD.

cell biology↗

bioRxiv2023

CLAIR: An integrated lipid database across multiple crop species

Oilseed crops, which are rich in plant lipids, provide essential fatty acids for human consumption and serve as major sources of biofuels and essential raw materials for the chemical industry. As a result of population growth and ecological changes, the demand for vegetable oil is increasingly outpacing supply. A comprehensive understanding of the genes involved in lipid metabolism in oilseed crops and the regulatory relationships among these genes is essential for improving oil content. However, current studies on lipid metabolism genes rely heavily on a decade-old database of genes involved in lipid metabolism in Arabidopsis thaliana. To address this issue, we mined the literature, integrated data from various databases and studies, and aligned homologs of lipid metabolism genes from nine oilseed crops to construct a comprehensive set of lipid metabolism genes in plants. Using this approach, we identified 221 additional lipid metabolism genes. In addition, we created a user-friendly lipid database called CLAIR (Crop Lipid-Associated Information Resource) by integrating and mining multi-omics data from nine major oil crops. The database is available at http://www.clipair.cn/. These resources should facilitate further research and exploration of lipid metabolism in oil crops, ultimately contributing to improved oil production.

plant biology↗

bioRxiv2023

Percolation Theory Used to Design Biomolecular Condensates

Biomolecular condensates formed by liquid-liquid phase separation (LLPS) are crucial for various life activities. Critical phenomena are observed during LLPS in cells and in vitro, but few studies provide quantitative theoretical explanations for them. In this study, we set up a Bethe network model to simulate percolation, which explains LLPS quantitatively and semi-quantitatively. We designed a condensate system to determine the peptides affinity to its target protein. Finally, we found that the artificial condensate can modify the catalytic reactions efficiency. Thus, we provide a new perspective on understanding biomolecular condensate assembly and lay the foundation for artificially designing biomolecular condensates.

biophysics↗

bioRxiv2023

A General Single-Cell Analysis Framework via Conditional Diffusion Generative Models

AO_SCPLOWBSTRACTC_SCPLOWThe fast-growing single-cell analysis community extends the horizon of quantitative analysis to numerous computational tasks. While the tasks hold vastly different targets from each other, existing works typically design specific model frameworks according to the downstream objectives. In this work, we propose a general single-cell analysis framework by unifying common computational tasks as posterior estimation problems. In light of conditional diffusion generative models, we introduce scDiff through the proposed framework and study different conditioning strategies. With data-specific conditions, scDiff achieves competitive performance against state-of-the-art in various benchmarking tasks. In addition, we illustrate the flexibility of scDiff by incorporating prior information through large language models and graph neural networks. Additional few-shot and zero-shot experiments prove the effectiveness of the prior conditioner on scDiff. Our implementation is publicly available at https://github.com/OmicsML/scDiff.

bioinformatics↗

bioRxiv2023

A chromosome-level reference genome of a Fabaceae species yam bean (Pachyrhizus erosus)

Yam bean (Pachyrhizus erosus L.), belonging to the family Fabaceae, is an important but underutilized root crop. Here, we generated a high-quality chromosome-level reference genome of yam bean by PacBio HiFi and Hi-C sequencing, with assembly size of 539.0 Mb, contig N50 of 25.6 Mb, and BUSCO complete rate of 99.3%. Then, we anchored 94.4% of the contig sequences into 11 pseudo-chromosomes, and assembled the telomeres at 86.4% (19/22) of the chromosome-ends. A total of 44,692 protein-coding genes were predicted, with the BUSCO complete rate of 99.3%, comparable to that of the genome assembly. Compared to the previously reported yam bean genome, the current assembly has a 1,388-fold increase in contig N50 size, and 12.2% and 24.3% increase in BUSCO complete rate for the genome sequence and gene set, respectively. Evolutionary analysis revealed that yam bean diverged from the clade of soybean and Pueraria lobata var. montana 22.5 MYA. This high-quality genome assembly will greatly facilitate the breeding of yam bean based on the genetic and genomic methods.

genomics↗

bioRxiv2023

Improved chromosome-level genome assembly for marigold (Tagetes erecta)

Marigold (Tagetes erecta L.) is a popular ornamental plant of the Asteraceae family, and its petals are considered the most abundant source of lutein. A low-continuity chromosome-level genome sequence of marigold was published recently, with poor annotation of the protein-coding genes, which hinders the studies of lutein biosynthesis. Here, we generated a near telomere-to-telomere level genome assembly of marigold based on highly accurate high-fidelity (HiFi) long reads and Hi-C sequencing data. Compared to the previously reported marigold genome, the current assembly had obviously higher contiguity and higher completeness of gene set. The current genome assembly has a 27-fold increase in contig N50 size, a 12.1% increase in chromosome anchoring rate, and a 9.0% increase in BUSCO complete rate for the gene set. Besides, the current assembly has much fewer assembly errors. Based on this high-quality genome assembly, we found that the 170-bp repeats are the most abundant centromeric unit and all centromeric regions are distributed along the whole chromosomes for all 12 centromeres, indicating the existence of the holocentromeres in marigold. In addition, we analyzed the structure and phylogenetic relationship of the four PSY genes, and revealed that these genes have diversified and possibly executed different functions in various tissues. Our near telomere-to-telomere level genome assembly and comprehensive gene annotation will greatly facilitate the breeding of marigold and researches aimed at improving lutein production.

genomics↗

bioRxiv2023

Metabolic Nutrient Preferences of Vibrio mimicus: Leveraging Nucleotides and Oligopeptides from Yellow Catfish for Enhanced Infectivity

In the context of host-microbe interactions, the microenvironment plays a critical role in facilitating microbial survival, and variations in these microenvironments may influence the pathogenicity of microorganisms. Vibrio mimicus, a major pathogen responsible for infections in aquatic animals, poses a substantial threat to yellow catfish (Pelteobagrus fulvidraco) and grass carp (Ctenopharyngodon idella), two naturally occurring hosts displaying markedly different susceptibility levels. This study aims to unravel the underlying mechanisms behind this susceptibility discrepancy in the two teleost species. Employing metabolomic analysis, we identified a distinctive microenvironment in yellow catfish, characterized by abundant purine nucleotides and oligopeptides. Furthermore, a total of 67 specific metabolites were identified from both yellow catfish and grass carp, with 33 displaying heightened expression on the body surface of yellow catfish, including nucleotides, amino acids, and gangliosides, while 34 were predominantly expressed on the body surface of grass carp, primarily comprising lipids. Subsequent investigations revealed that certain compounds related to nucleotides and oligopeptides exhibited significant growth-promoting effects and were utilized by V. mimicus as nutrients, with deoxyguanosine proving to be notably more than twice as effective as glucose. Moreover, during V. mimicus infection, numerous metabolites such as oligopeptides, purine nucleotides, and specific metabolites experienced considerable depletion in the skin of yellow catfish. Concurrently, several genes associated with nucleosidase and peptidase were upregulated in the skin and muscles of infected fish. These findings suggest that the microenvironment provided by different hosts plays a pivotal role in determining the infectivity of the pathogen. Additionally, our results indicate that the microenvironment on the surface of yellow catfish, characterized by an abundance of purine nucleotides and oligopeptides, indirectly enhances V. mimicus growth, ultimately augmenting its infectivity.

microbiology↗

bioRxiv2023

ESQmodel: biologically informed evaluation of 2-D cell segmentation quality in multiplexed tissue images

MotivationSingle cell segmentation is critical in the processing of spatial omics data to accurately perform cell type identification and analyze spatial expression patterns. Segmentation methods often rely on semi-supervised annotation or labeled training data which are highly dependent on user expertise. To ensure the quality of segmentation, current evaluation strategies quantify accuracy by assessing cellular masks or through iterative inspection by pathologists. While these strategies each address either the statistical or biological aspects of segmentation, there lacks an unified approach to evaluating segmentation accuracy. ResultsIn this paper, we present ESQmodel, a Bayesian probabilistic method to evaluate single cell segmentation using expression data. By using the extracted cellular data from segmentation and a prior belief of cellular composition as input, ESQmodel computes per cell entropy to assess segmentation quality by how consistent cellular expression profiles match with cell type expectations. Availability and implementationSource code is available on Github at: https://github.com/Roth-Lab/ESQmodel under the MIT license.

bioinformatics↗

bioRxiv2023

High-level production of nervonic acid in the oleaginous yeast Yarrowia lipolytica by systematic metabolic engineering

Brain and neurological diseases are influencing more than one billion worlds people. Nervonic acid (cis-15-tetracosenoic acid, C24:1 {Delta}15) benefits the treatment of neurological diseases and the health of brain. Currently, the sources of nervonic acid are limited to the seeds of a couple of plants. In this study, we employed the oleaginous yeast Yarrowia lipolytica to overproduce nervonic acid oil by systematic metabolic engineering. First, engineering the fatty acid elongation (FAE) pathway by expressing a heterologous {beta}-ketoacyl-CoA synthase gene CgKCS enabled the production of nervonic acid in Y. lipolytica. Second, modulation of endogenous pathways by expressing a C16:0-acyl-CoA preferred fatty acid elongase gELOVL6 together with a C18:0-acyl-CoA preferred fatty acid desaturase MaOLE2 increased the content of nervonic acid in total fatty acids (TFA). Third, iterative expression of CgKCS, gELOVL6 and MaOLE2 at the genomic loci of rDNA, FAD2, TGL4, GSY1 and SNF1 dramatically improved the production of nervonic acid. Fourth, the biosynthesis of both nervonic acid and lipids were further enhanced by expression of the MaOLE2-CgKCS fusion protein and glycerol-3-phosphate acyltransferases (GPAT) and diacylglycerol acyltransferases (DGAT) from Malania oleifera in the endoplasmic reticulum (ER) membrane. Fifth, an ER structure regulator YlINO2 was identified in Y. lipolytica and the overexpression of YlINO2 led to a 39.3% increase in lipid production. Next, pilot-scale fermentation in 50-L reactor using the strain YLNA9 exhibited a lipid titer of 96.7 g/L and a nervonic acid titer of 17.3 g/L, the highest reported titer to date for de novo nervonic acid production. We also found that disruption of the AMP-activated S/T protein kinase SNF1 increased the ratio of nervonic acid (C24:1) to lignoceric acid (C24:0) by 61.6% and a ratio of 3.5:1 (nervonic acid to lignoceric acid) was achieved in the strain YLNA10. Finally, a proof-of-concept purification and separation of nervonic acid were performed and the purity of it reached 98.7%. This study suggested that oleaginous yeasts are attractive hosts for the cost-efficient production of nervonic acid and possibly other very long-chain fatty acids (VLCFAs).

bioengineering↗

bioRxiv2023

LY6E protects mice from pathogenic effects of murine coronavirus and SARS-CoV-2

LY6E is an antiviral protein that inhibits coronavirus entry. Its expression in immune cells allows mice to control murine coronavirus infection. However, it is not known which immune cell subsets mediate this control or whether LY6E protects mice from SARS-CoV-2. In this study, we used tissue-specific Cre recombinase expression to ablate Ly6e in distinct immune compartments or in all epiblast-derived cells, and bone marrow chimeras to target Ly6e in a subset of radioresistant cells. Mice lacking Ly6e in Lyz2-expressing cells and radioresistant Vav1-expressing cells were more susceptible to lethal murine coronavirus infection. Mice lacking Ly6e globally developed clinical disease when challenged with the Gamma (P.1) variant of SARS-CoV-2. By contrast, wildtype mice and mice lacking type I and type III interferon signaling had no clinical symptoms after SARS-CoV-2 infection. Transcriptomic profiling of lungs from SARS-CoV-2-infected wildtype and Ly6e knockout mice revealed a striking reduction of secretory cell-associated genes in infected knockout mice, including Muc5b, an airway mucin-encoding gene that may protect against SARS-CoV-2-inflicted respiratory disease. Collectively, our study reveals distinct cellular compartments in which Ly6e confers cell intrinsic antiviral effects, thereby conferring resistance to disease caused by murine coronavirus and SARS-CoV-2.

microbiology↗

bioRxiv2023

Illumination of the complement receptors C3aR and C5aR signaling by anaphylatoxins

The complement receptors C3aR and C5aR, whose signaling are selectively activated by anaphylatoxins C3a and C5a, are important regulators of both innate and adaptive immune responses. Dysregulations of C3aR and C5aR signaling lead to multiple inflammatory disorders, including sepsis, asthma, and acute respiratory distress syndrome (ARDS). The mechanism underlying endogenous anaphylatoxin recognition and activation of C3aR and C5aR remains elusive. Here we reported the structures of C3a-bound C3aR and C5a-bound C5aR1 as well as an apo C3aR structure. These structures, combined with mutagenesis analysis, reveal a conserved recognition pattern of anaphylatoxins to the complement receptors that is different from chemokine receptors, unique pocket topologies of C3aR and C5aR1 that mediate ligand selectivity, and a common mechanism of receptor activation. These results provide crucial insights into the molecular understandings of C3aR and C5aR1 signaling and structural templates for rational drug design for treating inflammation disorders.

biochemistry↗

bioRxiv2023

Rice potassium transporter OsHAK18 mediates phloem K+ loading and redistribution

High-Affinity K+ transporters/K+ Uptake Permeases/K+ Transporters (HAK/KUP/KT) are important pathways mediating K+ transport across cell membrane, which function in maintaining K+ homeostasis during plant growth and stress response. An increasing number of studies have shown that HAK/KUP/KT transporters play important roles in potassium uptake and root-to-shoot translocation. However, whether some HAK/KUP/KT transporters mediate K+ redistribution in phloem remains unknown. In this study, we revealed that a phloem-localized HAK/KUP/KT transporter, OsHAK18 operated as a typical KUP/HAK/KT transporter mediating cell K+ uptake when expressed in yeast, E. coli and Arabidopsis. It was localized at plasma membrane. Disruption of OsHAK18 rendered rice seedlings insensitive to low-K+ stress. Compared with WT, the oshak18 mutants accumulated more K+ in shoots but less K+ in roots, leading to a higher shoot/root ratio of K+ per plant. Although disruption of OsHAK18 doesnt affect root K+ uptake and K+ level in xylem sap, it significantly decreases phloem K+ concentration and inhibits root-to-shoot-to-root K+ translocation in split-root assay. These results reveal that OsHAK18 mediates phloem K+ loading and redistribution, whose disruption is favor of shoot K+ retention under low-K+ stress. Our findings not only reveal a unique function of rice HAK/KUP/KT family member, but also provide a promising strategy to improve rice tolerance under K+ deficiency.

plant biology↗

bioRxiv2022

Horizontal transferred T-DNA and haplotype-based phylogenetic analysis uncovers the origin of sweetpotato

The hexaploid sweetpotato is one of the most important root crops worldwide. However, its genetic origins are controversial. In this study, we identified two progenitors of sweetpotato by horizontal gene transferred IbT-DNA and haplotype-based phylogenetic analysis. The diploid progenitor is the diploid form of I. aequatoriensis, contributed the B1 subgenome, IbT-DNA2 and lineage 2 type of chloroplast genome to sweetpotato. The tetraploid progenitor of sweetpotato is I. batatas 4x, donating the B2 subgenome, IbT-DNA1 and lineage 1 type of chloroplast genome. Sweetpotato derived from the reciprocal cross between the diploid and tetraploid progenitors and a subsequent whole genome duplication. We also detected biased gene exchanges between subgenomes. The B1 to B2 subgenome conversions were almost 3-fold higher than the B2 to B1 subgenome conversions. This study sheds lights on the evolution of sweetpotato and paves a way for the improvement of sweetpotato.

evolutionary biology↗

bioRxiv2022

Subchronic oral toxicity study of Aldicarb sulfoxide in Sprague-Dawley rats

Aldicarb sulfoxide is the metabolite of the exceedingly deadly carbamate insecticide Aldicarb. Aldicarb sulfoxide is easily soluble in water and has been identified in groundwater. Moreover, Aldicarb sulfoxide is highly hazardous to mammals. However, the toxicity data of Aldicarb sulfoxide is scarce. Here, the effects of relatively low dosages of exposure to Aldicarb sulfoxide on the blood biochemical, hematological, and histopathological parameters were examined in SD rats. The rats were treated with Aldicarb sulfoxide orally at dosages of 0, 6.3, 18.9, and 56.7 g per kg b.w. daily for 12 weeks. The results revealed that Aldicarb sulfoxide induced significant alterations in liver-related biochemical parameters, glucose level, cholesterol level, and uric acid level. Histopathological testing demonstrated cellular alterations in the liver of 18.9 and 56.7 g/kg BW. Together, our data demonstrated that Aldicarb sulfoxide exposure causes liver injury. Furthermore, the no observed adverse effect level (NOAEL) was less than 6.3 g/kg BW, and the lowest benchmark dose (BMD) value was 0.03 g/kg BW. Accordingly, Aldicarb sulfoxides derived no-effect level (DNEL) was calculated as 0.00035 g/kg BW. Thus, this work is an important reference for supervising Aldicarb sulfoxide in the environment and determining safe exposure limits for Aldicarb sulfoxide.

pharmacology and toxicology↗

bioRxiv2022

Intrinsic and extrinsic inhibition of cortical flow underlies symmetry breaking during unilateral cytokinesis

The contractile ring plays crucial roles in animal morphogenesis. Previous studies have explored how tissue mechanics controls the contractile ring; however, the mechanisms by which the ring senses tissue mechanics remain largely unknown. Here, we demonstrate the mechanism of contractile ring mechanosensation and its tuning during asymmetric ring closure of Caenorhabditis elegans embryos. High-resolution imaging of cortical flow revealed that local suppression of the ring-directed cortical flow is associated with a delay in furrowing. This suppression of cortical flow results from cortical compression. We found that the artificial inhibition of ring-directed cortical flow was sufficient to induce asymmetric ring closure in symmetrically dividing cells. Moreover, genetic analysis suggests that the positive feedback loop among ring-directed cortical flow, myosin enrichment, and ring constriction constitutes the anillin-dependent, mechanosensitive engine driving asymmetric ring closure. Our results suggest that the balance between RhoA-dependent and cortical flow-dependent myosin enrichment fine-tunes the rings mechanosensitivity in tissues.

cell biology↗

bioRxiv2022

FGF21 Counteracts Alcohol Intoxication by Activating Noradrenergic Neurons

Animals that consume fermenting fruit or nectar are exposed to ethanol, thus increasing their risk of injury or predation. This risk is heightened in humans, who have actively imbibed alcohol for thousands of years. In this report, we show that the hormone FGF21, which is strongly induced by ethanol in murine and human liver, exerts sobering or "amethystic" effects on both arousal and motor coordination without changing ethanol catabolism. Mice lacking FGF21 take longer than wild-type littermates to recover their righting reflex and balance following ethanol exposure. Conversely, pharmacologic FGF21 administration reduces the time needed for mice to recover from ethanol-induced unconsciousness and ataxia. FGF21 mediates it amethystic effects by directly activating the noradrenergic nervous system, which regulates arousal and alertness. These results indicate that this FGF21 liver-brain pathway evolved to protect against ethanolinduced intoxication and that it might be targeted pharmaceutically for treating acute alcohol poisoning.

neuroscience↗