[en] Clostridioides difficile infection (CDI) appears to be associated with different liver diseases. C. difficile secretes membrane vesicles (MVs), which may be involved in the development of nonalcoholic fatty liver disease (NALFD) and drug-induced liver injury (DILI). In this study, we investigated the presence of C. difficile-derived MVs in patients with and without CDI, and analyzed their effects on pathways related to NAFLD and DILI in HepG2 cells. Fecal extracellular vesicles from CDI patients showed an increase of Clostridioides MVs. C. difficile-derived MVs that were internalized by HepG2 cells. Toxigenic C. difficile-derived MVs decreased mitochondrial membrane potential and increased intracellular ROS compared to non-toxigenic C. difficile-derived MVs. In addition, toxigenic C. difficile-derived MVs upregulated the expression of genes related to mitochondrial fission (FIS1 and DRP1), antioxidant status (GPX1), apoptosis (CASP3), glycolysis (HK2, PDK1, LDHA and PKM2) and β-oxidation (CPT1A), as well as anti- and pro-inflammatory genes (IL-6 and IL-10). However, non-toxigenic C. difficile-derived MVs did not produce changes in the expression of these genes, except for CPT1A, which was also increased. In conclusion, the metabolic and mitochondrial changes produced by MVs obtained from toxigenic C. difficile present in CDI feces are common pathophysiological features observed in the NAFLD spectrum and DILI.
Research Center/Unit :
FARAH. Santé publique vétérinaire - ULiège
Disciplines :
Immunology & infectious disease
Author, co-author :
Caballano-Infantes, Estefanía ; Department of Regeneration and Cell Therapy Andalusian, Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, Junta de Andalucía, 41092 Seville, Spain
Ho-Plágaro, Ailec; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
López-Gómez, Carlos ; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
Martín-Reyes, Flores ; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
Rodríguez-Pacheco, Francisca; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
Taminiau, Bernard ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Daube, Georges ; Université de Liège - ULiège > Département de sciences des denrées alimentaires (DDA) > Microbiologie des denrées alimentaires
Garrido-Sánchez, Lourdes; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain ; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain
Alcaín-Martínez, Guillermo; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
Andrade, Raúl J. ; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain ; Departamento de Medicina, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain ; CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain
García-Cortés, Miren; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain ; Departamento de Medicina, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain ; CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain
Lucena, M. Isabel ; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain ; Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Departamento de Farmacología, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain ; UICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Málaga, Spain
García-Fuentes, Eduardo ; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain ; CIBER de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain
Rodriguez Diaz, Cristina ; Université de Liège - ULiège > Département de sciences des denrées alimentaires (DDA) ; Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, 29010 Málaga, Spain ; UGC de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
ISCIII - Instituto de Salud Carlos III FEDER - Fonds Européen de Développement Régional Junta de Andalucía. Consejería de Economía, Conocimiento, Empresas y Universidad
Funding text :
FEDER funds (“A way to make Europe”); Nicolas Monardes program from the Consejería de Salud de Andalucía
Jiang L. Schnabl B. Gut Microbiota in Liver Disease: What Do We Know and What Do We Not Know? Physiology 2020 35 261 274 10.1152/physiol.00005.2020 32490750
Xu M. Luo K. Li J. Li Y. Zhang Y. Yuan Z. Xu Q. Wu X. Role of Intestinal Microbes in Chronic Liver Diseases Int. J. Mol. Sci. 2022 23 12661 10.3390/ijms232012661 36293518
Rodriguez-Diaz C. Taminiau B. García-García A. Cueto A. Robles-Díaz M. Ortega-Alonso A. Martín-Reyes F. Daube G. Sanabria-Cabrera J. Jimenez-Perez M. et al. Microbiota diversity in nonalcoholic fatty liver disease and in drug-induced liver injury Pharmacol. Res. 2022 182 106348 10.1016/j.phrs.2022.106348 35817360
Gupta H. Min B.H. Ganesan R. Gebru Y.A. Sharma S.P. Park E. Won S.M. Jeong J.J. Lee S.B. Cha M.G. et al. Gut microbiome in non-alcoholic fatty liver disease: From mechanisms to therapeutic role Biomedicines 2022 10 550 10.3390/biomedicines10030550
Aron-Wisnewsky J. Gaborit B. Dutour A. Clement K. Gut microbiota and non-alcoholic fatty liver disease: New insights Clin. Microbiol. Infect. 2013 19 338 348 10.1111/1469-0691.12140
Rodriguez C. Van Broeck J. Taminiau B. Delmée M. Daube G. Clostridium difficile infection: Early history, diagnosis and molecular strain typing methods Microb. Pathog. 2016 97 59 78 10.1016/j.micpath.2016.05.018
Blanchi J. Goret J. Mégraud F. Clostridium difficile Infection: A Model for Disruption of the Gut Microbiota Equilibrium Dig. Dis. 2016 34 217 220 10.1159/000443355
Nicholas A. Jeon H. Selasi G.N. Na S.H. Kwon H.I. Kim Y.J. Choi C.W. Kim S.I. Lee J.C. Clostridium difficile-derived membrane vesicles induce the expression of pro-inflammatory cytokine genes and cytotoxicity in colonic epithelial cells in vitro Microb. Pathog. 2017 107 6 11 10.1016/j.micpath.2017.03.006
Caruana J.C. Walper S.A. Bacterial Membrane Vesicles as Mediators of Microbe—Microbe and Microbe—Host Community Interactions Front. Microbiol. 2020 11 432 10.3389/fmicb.2020.00432
Koeppen K. Hampton T.H. Jarek M. Scharfe M. Gerber S.A. Mielcarz D.W. Demers E.G. Dolber E.L. Hammond J.H. Hogan D.A. et al. A Novel Mechanism of host-pathogen interaction through sRNA in bacterial outer membrane vesicles PLoS Pathog. 2016 12 e1005672 10.1371/journal.ppat.1005672
Díaz-Garrido N. Bonnin S. Riera M. Gíménez R. Badia J. Baldomà L. Transcriptomic microRNA Profiling of Dendritic Cells in Response to Gut Microbiota-Secreted Vesicles Cells 2020 9 1534 10.3390/cells9061534 32585977
Lee J.H. Choi J.P. Yang J. Won H.K. Park C.S. Song W.J. Kwon H.S. Kim T.B. Kim Y.K. Park H.S. et al. Metagenome analysis using serum extracellular vesicles identified distinct microbiota in asthmatics Sci. Rep. 2020 10 15125 10.1038/s41598-020-72242-w 32934287
Rodríguez-Díaz C. Martín-Reyes F. Taminiau B. Ho-Plágaro A. Camargo R. Fernandez-Garcia F. Pinazo-Bandera J. Toro-Ortiz J.P. Gonzalo M. López-Gómez C. et al. The Metagenomic Composition and Effects of Fecal-Microbe-Derived Extracellular Vesicles on Intestinal Permeability Depend on the Patient’s Disease Int. J. Mol. Sci. 2023 24 4971 10.3390/ijms24054971
Choi J.W. Um J.H. Cho J.H. Lee H.J. Tiny RNAs and their voyage via extracellular vesicles: Secretion of bacterial small RNA and eukaryotic microRNA Exp. Biol. Med. 2017 242 1475 1481 10.1177/1535370217723166 28741379
Aktories K. Papatheodorou P. Schwan C. Binary Clostridium difficile toxin (CDT)—A virulence factor disturbing the cytoskeleton Anaerobe 2018 53 21 29 10.1016/j.anaerobe.2018.03.001 29524654
Jiang Y. Kong Q. Roland K.L. Curtiss R. 3rd Membrane vesicles of Clostridium perfringens type A strains induce innate and adaptive immunity Int. J. Med. Microbiol. 2014 304 431 443 10.1016/j.ijmm.2014.02.006 24631214
McMillan H.M. Kuehn M.J. The extracellular vesicle generation paradox: A bacterial point of view Embo J. 2021 40 e108174 10.15252/embj.2021108174 34636061
Zhang Y. Tan J. Miao Y. Zhang Q. The effect of extracellular vesicles on the regulation of mitochondria under hypoxia Cell Death Dis. 2021 12 358 10.1038/s41419-021-03640-9
Trifan A. Stoica O. Stanciu C. Cojocariu C. Singeap A.M. Girleanu I. Miftode E. Clostridium difficile infection in patients with liver disease: A review Eur. J. Clin. Microbiol. Infect. Dis. 2015 34 2313 2324 10.1007/s10096-015-2501-z
Šamadan L. Jeličić M. Vince A. Papić N. Nonalcoholic Fatty Liver Disease-A Novel Risk Factor for Recurrent Clostridioides difficile Infection Antibiotics 2021 10 780 10.3390/antibiotics10070780
Lee S. Lee H. Kim S. Lee J. Ha J. Choi Y. Oh H. Kim Y. Lee Y. Choi K.H. et al. Intestinal Clostridioides difficile Can Cause Liver Injury through the Occurrence of Inflammation and Damage to Hepatocytes Biomed. Res. Int. 2020 2020 7929610 10.1155/2020/7929610
Zhang C. Zhao Y. Yu M. Qin J. Ye B. Wang Q. Mitochondrial Dysfunction and Chronic Liver Disease Curr. Issues Mol. Biol. 2022 44 3156 3165 10.3390/cimb44070218 35877442
McKay D.M. Mancini N.L. Shearer J. Shutt T. Perturbed mitochondrial dynamics, an emerging aspect of epithelial-microbe interactions Am. J. Physiol. Gastrointest. Liver Physiol. 2020 318 G748 G762 10.1152/ajpgi.00031.2020 32116020
Lagos L. Leanti La Rosa S. Ø Arntzen M. Ånestad R. Terrapon N. Gaby J.C. Westereng B. Isolation and Characterization of Extracellular Vesicles Secreted In Vitro by Porcine Microbiota Microorganisms 2020 8 983 10.3390/microorganisms8070983 32630095
Dauros Singorenko P. Chang V. Whitcombe A. Simonov D. Hong J. Phillips A. Swift S. Blenkiron C. Isolation of membrane vesicles from prokaryotes: A technical and biological comparison reveals heterogeneity J. Extracell. Vesicles. 2017 6 1324731 10.1080/20013078.2017.1324731
Mehanny M. Koch M. Lehr C.M. Fuhrmann G. Streptococcal Extracellular Membrane Vesicles Are Rapidly Internalized by Immune Cells and Alter Their Cytokine Release Front. Immunol. 2020 11 80 10.3389/fimmu.2020.00080
Gérard A. El-Hajjaji S. Burteau S. Fall P.A. Pirard B. Taminiau B. Daube G. Sindic M. Study of the microbial diversity of a panel of Belgian artisanal cheeses associated with challenge studies for Listeria monocytogenes Food Microbiol. 2021 100 103861 10.1016/j.fm.2021.103861
Rognes T. Flouri T. Nichols B. Quince C. Mahé F. VSEARCH: A versatile open source tool for metagenomics PeerJ 2016 4 e2584 10.7717/peerj.2584
Schloss P.D. Westcott S.L. Ryabin T. Hall J.R. Hartmann M. Hollister E.B. Lesniewski R.A. Oakley B.B. Parks D.H. Robinson C.J. et al. Introducing mothur: Open-source, platform-independent, community-supported software for describing and comparing microbial communities Appl. Environ. Microbiol. 2009 75 7537 7541 10.1128/AEM.01541-09
Fernandes A.D. Reid J.N. Macklaim J.M. McMurrough T.A. Edgell D.R. Gloor G.B. Unifying the analysis of high-throughput sequencing datasets: Characterizing RNA-seq, 16S rRNA gene sequencing and selective growth experiments by compositional data analysis Microbiome 2014 2 15 10.1186/2049-2618-2-15
Rodriguez C. Taminiau B. Van Broeck J. Avesani V. Delmée M. Daube G. Clostridium difficile in young farm animals and slaughter animals in Belgium Anaerobe 2012 18 621 625 10.1016/j.anaerobe.2012.09.008 23041559
Indra A. Huhulescu S. Schneeweis M. Hasenberger P. Kernbichler S. Fiedler A. Wewalka G. Allerberger F. Kuijper E.J. Characterization of Clostridium difficile isolates using capillary gel electrophoresis-based PCR ribotyping J. Med. Microbiol. 2008 57 Pt 11 1377 1382 10.1099/jmm.0.47714-0 18927415
Rodriguez C. Avesani V. Van Broeck J. Taminiau B. Delmée M. Daube G. Presence of Clostridium difficile in pigs and cattle intestinal contents and carcass contamination at the slaughterhouse in Belgium Int. J. Food Microbiol. 2013 166 256 262 10.1016/j.ijfoodmicro.2013.07.017 23973837
Patten D.A. Hussein E. Davies S.P. Humphreys P.N. Collett A. Commensal-derived OMVs elicit a mild proinflammatory response in intestinal epithelial cells Microbiology 2017 163 702 711 10.1099/mic.0.000468
Brandes V. Schelle I. Brinkmann S. Schulz F. Schwarz J. Gerhard R. Genth H. Protection from Clostridium difficile toxin B-catalysed Rac1/Cdc42 glucosylation by tauroursodeox-ycholic acid-induced Rac1/Cdc42 phosphorylation Biol. Chem. 2012 393 77 84 10.1515/BC-2011-198 22628301
Ligasová A. Koberna K. Quantification of fixed adherent cells using a strong enhancer of the fluorescence of DNA dyes Sci. Rep. 2019 9 8701 10.1038/s41598-019-45217-9
Cummings B.S. Schnellmann R.G. Measurement of cell death in mammalian cells Curr. Protoc. Pharmacol. 2004 25 12.8.1 12.8.22 10.1002/0471141755.ph1208s25
Antharam V.C. Li E.C. Ishmael A. Sharma A. Mai V. Rand K.H. Wang G.P. Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile infection and nosocomial diarrhea J. Clin. Microbiol. 2013 51 2884 2892 10.1128/JCM.00845-13
Dong D. Ni Q. Wang C. Zhang L. Li Z. Jiang C. Mao E. Peng Y. Effects of intestinal colonization by Clostridium difficile and Staphylococcus aureus on microbiota diversity in healthy individuals in China BMC Infect. Dis. 2018 18 207 10.1186/s12879-018-3111-z
Dicks L.M.T. Mikkelsen L.S. Brandsborg E. Marcotte H. Clostridium difficile, the Difficult “Kloster” Fuelled by Antibiotics Curr. Microbiol. 2019 76 774 782 10.1007/s00284-018-1543-8
Azimirad M. Krutova M. Balaii H. Kodori M. Shahrokh S. Azizi O. Yadegar A. Aghdaei H.A. Zali M.R. Coexistence of Clostridioides difficile and Staphylococcus aureus in gut of Iranian outpatients with underlying inflammatory bowel disease Anaerobe 2020 61 102113 10.1016/j.anaerobe.2019.102113 31698044
Vincent C. Manges A.R. Antimicrobial Use, Human Gut Microbiota and Clostridium difficile Colonization and Infection Antibiotics 2015 4 230 253 10.3390/antibiotics4030230 27025623
Ju T. Kong J.Y. Stothard P. Willing B.P. Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota ISME J. 2019 13 1520 1534 10.1038/s41396-019-0364-5
Schadt H.S. Wolf A. Pognan F. Chibout S.D. Merz M. Kullak-Ublick G.A. Bile acids in drug induced liver injury: Key players and surrogate markers Clin. Res. Hepatol. Gastroenterol. 2016 40 257 266 10.1016/j.clinre.2015.12.017
Gottlieb A. Canbay A. Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression Cells 2019 8 1358 10.3390/cells8111358 31671697
Villanueva-Paz M. Morán L. López-Alcántara N. Freixo C. Andrade R.J. Lucena M.I. Cubero F.J. Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice Antioxidants 2021 10 390 10.3390/antiox10030390
Park J.W. Kim S.E. Lee N.Y. Kim J.H. Jung J.H. Jang M.K. Park S.H. Lee M.S. Kim D.J. Kim H.S. et al. Role of Microbiota-Derived Metabolites in Alcoholic and Non-Alcoholic Fatty Liver Diseases Int. J. Mol. Sci. 2021 23 426 10.3390/ijms23010426
Richard J.F. Petit L. Gibert M. Marvaud J.C. Bouchaud C. Popoff M.R. Bacterial toxins modifying the actin cytoskeleton Int. Microbiol. 1999 2 185 194
Buddle J.E. Fagan R.P. Pathogenicity and virulence of Clostridioides difficile Virulence 2023 14 2150452 10.1080/21505594.2022.2150452 36419222
Jiang Y. Chowdhury S. Xu B.H. Meybodi M.A. Damiris K. Devalaraju S. Pyrsopoulos N. Nonalcoholic fatty liver disease is associated with worse intestinal complications in patients hospitalized for Clostridioides difficile infection World J. Hepatol. 2021 13 1777 1790 10.4254/wjh.v13.i11.1777
Liu Y. Chen M. Clostridioides difficile Infection in Liver Cirrhosis: A Concise Review Can. J. Gastroenterol. Hepatol. 2022 2022 4209442 10.1155/2022/4209442 35711246
Cai D.H. Chen B.H. Liu Q.Y. Le X.Y. He L. Synthesis, structural studies, interaction with DNA/HSA and antitumor evaluation of new Cu(II) complexes containing 2-(1H-imidazol-2-yl)pyridine and amino acids Dalton Trans. 2022 51 16574 16586 10.1039/D2DT02985E 36263706
Jin S.M. Lazarou M. Wang C. Kane L.A. Narendra D.P. Youle R.J. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL J. Cell. Biol. 2010 191 933 942 10.1083/jcb.201008084
Deo P. Chow S.H. Hay I.D. Kleifeld O. Costin A. Elgass K.D. Jiang J.H. Ramm G. Gabriel K. Dougan G. et al. Outer membrane vesicles from Neisseria gonorrhoeae target PorB to mitochondria and induce apoptosis PLoS Pathog. 2018 14 e1006945 10.1371/journal.ppat.1006945
To E.E. O’Leary J.J. O’Neill L.A.J. Vlahos R. Bozinovski S. Porter C.J.H. Brooks R.D. Brooks D.A. Selemidis S. Spatial Properties of Reactive Oxygen Species Govern Pathogen-Specific Immune System Responses Antioxid. Redox Signal. 2020 32 982 992 10.1089/ars.2020.8027
Brigelius-Flohé R. Maiorino M. Glutathione peroxidases Biochim. Biophys. Acta 2013 1830 3289 3303 10.1016/j.bbagen.2012.11.020
Fondevila M.F. Fernandez U. Heras V. Parracho T. Gonzalez-Rellan M.J. Novoa E. Porteiro B. Alonso C. Mayo R. da Silva Lima N. et al. Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis J. Hepatol. 2022 77 15 28 10.1016/j.jhep.2022.02.003
Sun W. Nie T. Li K. Wu W. Long Q. Feng T. Mao L. Gao Y. Liu Q. Gao X. et al. Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice Diabetes 2021 71 31 42 10.2337/db21-0363
Chen Z. Tian R. She Z. Cai J. Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease Free. Radic. Biol. Med. 2020 152 116 141 10.1016/j.freeradbiomed.2020.02.025
Wai T. Langer T. Mitochondrial Dynamics and Metabolic Regulation Trends Endocrinol. Metab. 2016 27 105 117 10.1016/j.tem.2015.12.001 26754340
Li Z. Berk M. McIntyre T.M. Gores G.J. Feldstein A.E. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity Hepatology 2008 47 1495 1503 10.1002/hep.22183 18220271
Katoh M. Wu B. Nguyen H.B. Thai T.Q. Yamasaki R. Lu H. Rietsch A.M. Zorlu M.M. Shinozaki Y. Saitoh Y. et al. Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation Sci. Rep. 2017 7 4942 10.1038/s41598-017-05232-0 28694451
Ramond E. Jamet A. Coureuil M. Charbit A. Pivotal Role of Mitochondria in Macrophage Response to Bacterial Pathogens Front. Immunol. 2019 10 2461 10.3389/fimmu.2019.02461 31708919
Legaki A.I. Moustakas I.I. Sikorska M. Papadopoulos G. Velliou R.I. Chatzigeorgiou A. Hepatocyte Mitochondrial Dynamics and Bioenergetics in Obesity-Related Non-Alcoholic Fatty Liver Disease Curr. Obes. Rep. 2022 11 126 143 10.1007/s13679-022-00473-1 35501558
Ramachandran A. Umbaugh D.S. Jaeschke H. Mitochondrial Dynamics in Drug-Induced Liver Injury Livers 2021 1 102 115 10.3390/livers1030010 34485975
Koliaki C. Szendroedi J. Kaul K. Jelenik T. Nowotny P. Jankowiak F. Herder C. Carstensen M. Krausch M. Knoefel W.T. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis Cell. Metab. 2015 21 739 746 10.1016/j.cmet.2015.04.004
Youle R.J. van der Bliek A.M. Mitochondrial fission, fusion, and stress Science 2012 337 1062 1065 10.1126/science.1219855
Rambold A.S. Pearce E.L. Mitochondrial Dynamics at the Interface of Immune Cell Metabolism and Function Trends Immunol. 2018 39 6 18 10.1016/j.it.2017.08.006
Lu Q. Tian X. Wu H. Huang J. Li M. Mei Z. Zhou L. Xie H. Zheng S. Metabolic Changes of Hepatocytes in NAFLD Front. Physiol. 2021 12 710420 10.3389/fphys.2021.710420
Trivedi P. Wang S. Friedman S.L. The Power of Plasticity-Metabolic Regulation of Hepatic Stellate Cells Cell. Metab. 2021 33 242 257 10.1016/j.cmet.2020.10.026
Xie M. Yu Y. Kang R. Zhu S. Yang L. Zeng L. Sun X. Yang M. Billiar T.R. Wang H. et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation Nat. Commun. 2016 7 13280 10.1038/ncomms13280 27779186
Palsson-McDermott E.M. Curtis A.M. Goel G. Lauterbach M.A. Sheedy F.J. Gleeson L.E. van den Bosch M.W. Quinn S.R. Domingo-Fernandez R. Johnston D.G. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages Cell. Metab. 2015 21 65 80 10.1016/j.cmet.2014.12.005 25565206
Chen X. Chen S. Yu D. Protein kinase function of pyruvate kinase M2 and cancer Cancer Cell. Int. 2020 20 523 10.1186/s12935-020-01612-1
Panasyuk G. Espeillac C. Chauvin C. Pradelli L.A. Horie Y. Suzuki A. Annicotte J.S. Fajas L. Foretz M. Verdeguer F. et al. PPARγ contributes to PKM2 and HK2 expression in fatty liver Nat. Commun. 2012 3 672 10.1038/ncomms1667
Inomata Y. Oh J.W. Taniguchi K. Sugito N. Kawaguchi N. Hirokawa F. Lee S.W. Akao Y. Takai S. Kim K.P. et al. Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis Int. J. Mol. Sci. 2022 23 5230 10.3390/ijms23095230
Liu J. Jiang S. Zhao Y. Sun Q. Zhang J. Shen D. Wu J. Shen N. Fu X. Sun X. et al. Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions J. Pathol. 2018 246 277 288 10.1002/path.5131 29971772
Wang T. Chen K. Yao W. Zheng R. He Q. Xia J. Li J. Shao Y. Zhang L. Huang L. et al. Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance J. Hepatol. 2021 74 1038 1052 10.1016/j.jhep.2020.11.028
Zorov D.B. Juhaszova M. Sollott S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release Physiol. Rev. 2014 94 909 950 10.1152/physrev.00026.2013
