Fibroblast Growth Factor 19 Improves LPS-Induced Lipid Disorder and Organ Injury by Regulating Metabolomic Characteristics in Mice

Abstract

Sepsis is extremely heterogeneous pathology characterized by complex metabolic changes. Fibroblast growth factor 19 (FGF19) is a well-known intestine-derived inhibitor of bile acid biosynthesis. However, it is largely unknown about the roles of FGF19 in improving sepsis-associated metabolic disorder and organ injury. In the present study, mice were intravenously injected recombinant human FGF19 daily for 7 days followed by lipopolysaccharide (LPS) administration. At 24 hours after LPS stimuli, sera were collected for metabolomic analysis. Ingenuity pathway analysis (IPA) network based on differential metabolites (DMs) was conducted. Here, metabolomic analysis revealed that FGF19 pretreatment reversed the increase of LPS-induced fatty acids. IPA network indicated that altered linoleic acid (LA) and gamma-linolenic acid (GLA) were involved in the regulation of oxidative stress and mitochondrial function and were closely related to reactive oxygen species (ROS) generation. Further investigation proved that FGF19 pretreatment decreased serum malondialdehyde (MDA) levels and increased serum catalase (CAT) levels. In livers, FGF19 suppressed the expression of inducible NO synthase (iNOS) and enhanced the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and hemeoxygenase-1 (HO-1). Finally, FGF19 pretreatment protected mice against LPS-induced liver, ileum, and kidney injury. Taken together, FGF19 alleviates LPS-induced organ injury associated with improved serum LA and GLA levels and oxidative stress, suggesting that FGF19 might be a promising target for metabolic therapy for sepsis.

Integrating Network Pharmacology and Metabolomics to Explore the Potential Mechanism of Pinolenic Acid against Atherosclerosis

“…Te AA, LA, and PPARα signaling pathways were tentatively identifed as the mechanisms by which PLA exerts its anti-AS efects based on GO and KEGG pathway enrichment analyses and existing literature reports. Given that AA and LA metabolisms signifcantly stimulate ROS generation leading to oxidative stress [30,31], the protective efects of PLA are likely related to oxidative stress.…”

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases

“…FGF19 inhibited bile acid synthesis by suppressing CYP7A1. In sceptic mice, pretreatment with FGF19 was protective against LPS-induced liver, ileum, and kidney injury [96]. Activation of bile acid receptors FXR and TGR5 altered the NLRP3 inflammasome and cAMP/PKA/CREB signaling to decrease sepsis [97,98].…”

Research Progress of Macromolecules in the Prevention and Treatment of Sepsis

“…FGF-19 can reduce the expression of linoleic acid (LA) and gamma linolenic acid, activate the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (HO-1) pathway, and inhibit the expression of iNOS, ROS, caspase-3, and cytochrome c, thereby alleviating lipid metabolism disorders, liver injury, and kidney injury in mice with LPS-induced sepsis [ 26 ].…”