Estrogen: the forgotten player in metaflammation

Abstract

Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases. In this study, we present a prediction of the differential proteins and signal transduction of estrogen in MIS through network pharmacology and review the validated studies on obesity, T2DM, AS, and NAFLD. Subsequently, we compared them to obtain valuable targets, identify current gaps, and provide perspectives for future research on the mechanisms of estrogen in metaflammation.

Keywords: antiinflammatory effects; estrogen; hormone replacement therapy (HRT); metabolic inflammatory syndrome; metaflammation; network pharmacology; pharmacological targets; sex differences.

FIGURE 1

The PPI network diagram of the intersected targets of four diseases, obesity, T2DM, AS, and NAFLD, associated with estrogen. In the (A–D) diagram, all targets are arranged from large to small according to the degree value, and each node represents a target. The larger the degree value, the larger the node size, the darker the color, and the inner circle is the core target. NR1I3 is a free node in the PPI network of the intersection target of estrogen and obesity. PRKCQ was a free node in the PPI network of the intersection target of estrogen and T2DM. NR1I3, CFTR, and HSD11B1 are free nodes in the PPI network of estrogen and NAFLD intersection targets. The free nodes were not displayed after the PPI network was processed by Cytoscape 3.9.1. (A) The intersected targets of estrogen and obesity. The core targets are SRC, ESR1, PTGS2, NR3C1, and CYP19A1. (B) The intersected targets of estrogen and T2DM. The core targets are SRC, ESR1, PTGS2, MMP-9, NR3C1, and CYP19A1. (C) The intersected targets of estrogen and AS. The core targets are PTGS2, SRC, ESR1, and CYP19A1. (D) The intersected targets of estrogen and NAFLD. The core targets are ESR1, PTGS2, CNR1. (E)The common targets in the Venn diagram were obtained for the four diseases and estrogen, respectively. (F) The PPI network diagram of the common targets in the intersected targets was obtained for the four diseases and estrogen, respectively. The outermost layer of each combination graph is the target; the blue node shows the number of diseases with a common target, the purple node shows the disease, and the line between the disease and the target represents the relationship. Abbreviations: AS, atherosclerosis; CFTR, CF transmembrane conductance regulator; CNR1, cannabinoid receptor 1; CYP19A1, cytochrome P450 family 19 subfamily A member 1; ESR1, estrogen receptor 1; HSD11B1, hydroxysteroid 11-beta dehydrogenase 1; MMP-9, matrix metalloproteinases-9; NAFLD, nonalcoholic fatty liver disease; NR1I3, nuclear receptor subfamily 1 group I member 3; NR3C1, nuclear receptor subfamily 3 group C member 1; PPI, protein-protein interaction; PRKCQ, protein kinase C theta; PTGS2, prostaglandin-endoperoxide synthase 2; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; T2DM, type 2 diabetes mellitus.

FIGURE 2

The GO analysis and Venn diagram of the intersected targets of four diseases, obesity, T2DM, AS, and NAFLD, associated with estrogen. (A). The enrichment results of BP, CC, and MF of the intersected targets of estrogen and obesity. (B) The enrichment results of BP, CC, and MF of the intersected targets of estrogen and T2DM. (C) The enrichment results of BP, CC, and MF of the intersected targets of estrogen and AS. (D) The enrichment results of BP, CC, and MF in the intersected targets of estrogen and NAFLD. (E) The BP Venn diagram of the common targets contained in the intersected targets was obtained by the four diseases and estrogen, respectively. (F) The CC Venn diagram of the common targets contained in the intersected targets was obtained by the four diseases and estrogen, respectively. (G) The MF Venn diagram of the common targets in the intersected targets was obtained by the four diseases and estrogen, respectively. Abbreviations: AS, atherosclerosis; BP, biological process; CC, cellular component; GO, gene ontology; MF, molecular function; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2 diabetes mellitus.

FIGURE 3

The KEGG bubble diagram and Venn diagram of the intersected targets of four diseases associated with estrogen. The abscissa is fold enrichment. (A) Results of the KEGG pathway analysis of the intersected targets of estrogen and obesity. (B) Results of the KEGG pathway analysis of the intersected targets of estrogen and T2DM. (C) Results of the KEGG pathway analysis of the intersected targets of estrogen and AS. (D) Results of the KEGG pathway analysis of the intersected targets of estrogen and NAFLD. (E) The KEGG Venn diagram of the intersected targets of the four diseases and estrogen were obtained, respectively. Abbreviations: AS, atherosclerosis; KEGG, Kyoto encyclopedia of genes and genomes; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2 diabetes mellitus.

FIGURE 4

The flowchart of our search strategy. Abbreviations: AS, atherosclerosis; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2 diabetes mellitus.

FIGURE 5

Diagram of validated mechanisms of estrogen on metaflammation in MIS. Macrophages, vascular endothelial cells, vascular smooth muscle cells, especially adipocytes, islet cells, and hepatocytes, are significant contributors to MIS. Estrogen regulates metaflammation mainly by affecting the NF-κB pathway via binding to receptors such as ERα, ERβ, ERRα, and GPER on these cells. The following proteins, such as cytochrome c, FPR2, and TNFR2, regulate IL-1β, MCP-1, MMP-9, VLDL, ICAM-1, and VCAM-1, etc. are regulated in this process. Solid lines denote items that have already been verified. The dashed lines indicate possible mechanisms. Downward red arrows indicate reduction or suppression, while upward red arrows indicate an increase or promotion. Gradient arrows indicate nuclear translocation. Abbreviations: ERRα, estrogen-related receptor alpha; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; FPR2, formyl peptide receptor 2; GPER, G protein-coupled estrogen receptor; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin-1 beta; MCP-1, monocyte chemoattractant protein-1; MIS, metabolic inflammatory syndrome; MMP-9, matrix metalloproteinases-9; NF-κB, nuclear factor kappa-B; TNFR2, tumor necrosis factor receptor 2; VCAM-1, vascular cell adhesion molecule 1; VLDL, very low-density lipoproteins.