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

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.

[1]  Dandan Hao,et al.  Free Fatty Acid Species Differentially Modulate the Inflammatory Gene Response in Primary Human Skeletal Myoblasts , 2021, Biology.

[2]  W. Wang,et al.  Metabolomics Analysis of the Development of Sepsis and Potential Biomarkers of Sepsis-Induced Acute Kidney Injury , 2021, Oxidative medicine and cellular longevity.

[3]  R. Zazula,et al.  Myristic Acid Serum Levels and Their Significance for Diagnosis of Systemic Inflammatory Response, Sepsis, and Bacteraemia , 2021, Journal of personalized medicine.

[4]  Hongmei Jiang,et al.  Epigallocatechin Gallate Can Protect Mice From Acute Stress Induced by LPS While Stabilizing Gut Microbes and Serum Metabolites Levels , 2021, Frontiers in Immunology.

[5]  Q. Xiao,et al.  FGF19 protects skeletal muscle against obesity‐induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT‐1/PGC‐α pathway , 2021, Journal of cellular and molecular medicine.

[6]  So Min Lee,et al.  Lipidomics reveals that acupuncture modulates the lipid metabolism and inflammatory interaction in a mouse model of depression , 2021, Brain, Behavior, and Immunity.

[7]  D. Sonne.  Mechanisms in Endocrinology : FXR signalling - a novel target in metabolic diseases. , 2021, European journal of endocrinology.

[8]  Saswata Talukdar,et al.  FGF19 and FGF21: In NASH we trust , 2020, Molecular metabolism.

[9]  B. Andersen,et al.  FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human , 2020, Frontiers in Endocrinology.

[10]  T. Spector,et al.  A reference map of potential determinants for the human serum metabolome , 2020, Nature.

[11]  Yucai Zhang,et al.  IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling , 2020, Cell Death & Disease.

[12]  C. Shu,et al.  Polyunsaturated Fatty Acid Diet and Upregulation of Lipoxin A4 Reduce the Inflammatory Response of Preeclampsia. , 2020, Journal of proteome research.

[13]  Jian Sun,et al.  Gut-liver crosstalk in sepsis-induced liver injury , 2020, Critical Care.

[14]  王春霞,et al.  Clinical value of fibroblast growth factor 19 in predicting gastrointestinal dysfunction in children with sepsis , 2020 .

[15]  J. Trotter,et al.  Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis. , 2020, Gastroenterology.

[16]  Tiangang Li,et al.  An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis , 2020, Nature Communications.

[17]  F. Ren,et al.  FGF19 alleviates palmitate-induced atrophy in C2C12 cells by inhibiting mitochondrial overload and insulin resistance. , 2020, International journal of biological macromolecules.

[18]  Kefeng Li,et al.  Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation , 2020, BMC Medicine.

[19]  Shengwei Jin,et al.  PCTR1 ameliorates lipopolysaccharide-induced acute inflammation and multiple organ damage via regulation of linoleic acid metabolism by promoting FADS1/FASDS2/ELOV2 expression and reducing PLA2 expression , 2020, Laboratory Investigation.

[20]  T. Ala-Kokko,et al.  1H NMR Based Metabolomics in Human Sepsis and Healthy Serum , 2020, Metabolites.

[21]  P. Carmeliet,et al.  Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis , 2020, EMBO molecular medicine.

[22]  Jisoo Lee,et al.  Metabolomics and the Microbiome as Biomarkers in Sepsis. , 2020, Critical care clinics.

[23]  Priscilla A T Pereira,et al.  Immunomodulatory activity of hyaluronidase is associated with metabolic adaptations during acute inflammation , 2019, Inflammation Research.

[24]  Jeffrey B Warner,et al.  Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury[S] , 2019, Journal of Lipid Research.

[25]  J. Turnbull,et al.  Omics Insights into Metabolic Stress and Resilience of Rats in Response to Short-term Fructose Overfeeding. , 2019, Molecular nutrition & food research.

[26]  Eden L. Romm,et al.  Recognition of early and late stages of bladder cancer using metabolites and machine learning , 2019, Metabolomics.

[27]  M. Karsdal,et al.  Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial. , 2019, Journal of hepatology.

[28]  R. M. Learned,et al.  Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis , 2019, Journal of Lipid Research.

[29]  T. Doetschman,et al.  n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer , 2019, Nutrients.

[30]  K. Dryahina,et al.  Kinetics of Myristic Acid Following Accidentally Induced Septic Response. , 2019, Prague medical report.

[31]  D. Shou,et al.  Metabolomics study of the hepatoprotective effect of Phellinus igniarius in chronic ethanol-induced liver injury mice using UPLC-Q/TOF-MS combined with ingenuity pathway analysis. , 2020, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[32]  F. Marson,et al.  Lipid profile associated with the systemic inflammatory response syndrome and sepsis in critically ill patients. , 2018, Nutrition.

[33]  D. Song,et al.  Catalase and nonalcoholic fatty liver disease , 2018, Pflügers Archiv - European Journal of Physiology.

[34]  Ye Tian,et al.  Fibroblast growth factor 19 protects the heart from oxidative stress-induced diabetic cardiomyopathy via activation of AMPK/Nrf2/HO-1 pathway. , 2018, Biochemical and biophysical research communications.

[35]  J. Trotter,et al.  NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial , 2018, The Lancet.

[36]  Yucai Zhang,et al.  Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[37]  S. Kliewer,et al.  FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. , 2017, Cell metabolism.

[38]  Alan E. Jones,et al.  Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 , 2017, Intensive Care Medicine.

[39]  Y. C. Long,et al.  Mechanistic target of rapamycin complex 1 is an essential mediator of metabolic and mitogenic effects of fibroblast growth factor 19 in hepatoma cells , 2016, Hepatology.

[40]  Hui Zhao,et al.  IL-1β inhibits β-Klotho expression and FGF19 signaling in hepatocytes. , 2016, American journal of physiology. Endocrinology and metabolism.

[41]  A. Sjöstedt,et al.  Metabolites in Blood for Prediction of Bacteremic Sepsis in the Emergency Room , 2016, PloS one.

[42]  Ji Luo,et al.  NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis , 2016, Nature.

[43]  S. Kingsmore,et al.  Human metabolic response to systemic inflammation: assessment of the concordance between experimental endotoxemia and clinical cases of sepsis/SIRS , 2015, Critical Care.

[44]  M. Fink.  Animal models of sepsis , 2013, Virulence.

[45]  M. Bauer,et al.  Metabolism, metabolome, and metabolomics in intensive care: is it time to move beyond monitoring of glucose and lactate? , 2013, American journal of respiratory and critical care medicine.

[46]  L. Holdt,et al.  Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients* , 2012, Critical care medicine.

[47]  S. Kliewer,et al.  FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis , 2011, Science.

[48]  Sushant Bhatnagar,et al.  Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis* , 2009, Journal of Biological Chemistry.

[49]  P. Carmeliet,et al.  Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia. , 2007, Blood.

[50]  K. Krause,et al.  The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. , 2007, Physiological reviews.

[51]  P. Calder.  Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients. , 2003, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[52]  M. A. Gülpınar,et al.  Endothelin receptor blockers reduce I/R-induced intestinal mucosal injury: role of blood flow. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[53]  I. Salmon,et al.  Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats. , 2002, Journal of the American Society of Nephrology : JASN.

[54]  H. Tazelaar,et al.  Effects of eicosapentaenoic and gamma-linolenic acids (dietary lipids) on pulmonary surfactant composition and function during porcine endotoxemia. , 2000, Chest.