{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T19:34:04Z","timestamp":1770060844265,"version":"3.49.0"},"reference-count":88,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cancer Prevention and Research Institute of Texas","award":["RP210213"],"award-info":[{"award-number":["RP210213"]}]},{"name":"Cancer Prevention and Research Institute of Texas","award":["17SDG33670306"],"award-info":[{"award-number":["17SDG33670306"]}]},{"name":"Cancer Prevention and Research Institute of Texas","award":["RRID:SCR_021637"],"award-info":[{"award-number":["RRID:SCR_021637"]}]},{"name":"American Heart Association","award":["RP210213"],"award-info":[{"award-number":["RP210213"]}]},{"name":"American Heart Association","award":["17SDG33670306"],"award-info":[{"award-number":["17SDG33670306"]}]},{"name":"American Heart Association","award":["RRID:SCR_021637"],"award-info":[{"award-number":["RRID:SCR_021637"]}]},{"name":"Texas A&amp;M University Health Science Center","award":["RP210213"],"award-info":[{"award-number":["RP210213"]}]},{"name":"Texas A&amp;M University Health Science Center","award":["17SDG33670306"],"award-info":[{"award-number":["17SDG33670306"]}]},{"name":"Texas A&amp;M University Health Science Center","award":["RRID:SCR_021637"],"award-info":[{"award-number":["RRID:SCR_021637"]}]},{"name":"Integrated Microscopy and Imaging Laboratory at the Texas A&amp;M College of Medicine","award":["RP210213"],"award-info":[{"award-number":["RP210213"]}]},{"name":"Integrated Microscopy and Imaging Laboratory at the Texas A&amp;M College of Medicine","award":["17SDG33670306"],"award-info":[{"award-number":["17SDG33670306"]}]},{"name":"Integrated Microscopy and Imaging Laboratory at the Texas A&amp;M College of Medicine","award":["RRID:SCR_021637"],"award-info":[{"award-number":["RRID:SCR_021637"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2\u2212\/\u2212 mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2\u2212\/\u2212 mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced VEGFR3 expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis.<\/jats:p>","DOI":"10.3390\/cells12040526","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T04:59:10Z","timestamp":1675659550000},"page":"526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Conjugated Bile Acids Promote Lymphangiogenesis by Modulation of the Reactive Oxygen Species\u2013p90RSK\u2013Vascular Endothelial Growth Factor Receptor 3 Pathway"],"prefix":"10.3390","volume":"12","author":[{"given":"Priyanka","family":"Banerjee","sequence":"first","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subhashree","family":"Kumaravel","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sukanya","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niyanshi","family":"Gaddam","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnny","family":"Odeh","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayla J.","family":"Bayless","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4869-3198","authenticated-orcid":false,"given":"Sanjukta","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14218\/JCTH.2018.00025","article-title":"Therapeutic Roles of Bile Acid Signaling in Chronic Liver Diseases","volume":"6","author":"Li","year":"2018","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.livres.2018.09.008","article-title":"Regulation of bile acid receptor activity","volume":"2","author":"Wan","year":"2018","journal-title":"Liver Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fmed.2020.00015","article-title":"Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases","volume":"7","author":"Meadows","year":"2020","journal-title":"Front. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4943","DOI":"10.3892\/ol.2017.6763","article-title":"Diagnostic value of serum bile acid composition patterns and serum glycocholic acid levels in cholangiocarcinoma","volume":"14","author":"Proungvitaya","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.3748\/wjg.v12.i22.3553","article-title":"Bile acid interactions with cholangiocytes","volume":"12","author":"Xia","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1126\/science.aav0173","article-title":"Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation","volume":"363","author":"Lee","year":"2019","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1016\/j.ajpath.2021.08.011","article-title":"Targeting Lymphangiogenesis and Lymph Node Metastasis in Liver Cancer","volume":"191","author":"Roy","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1055\/s-0040-1713675","article-title":"The Role of Lymphatics in Cholestasis: A Comprehensive Review","volume":"40","author":"Gasheva","year":"2020","journal-title":"Semin. Liver Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.coi.2018.04.028","article-title":"Lymphatics in the liver","volume":"53","author":"Tanaka","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E94","DOI":"10.1111\/j.1749-6632.2010.05752.x","article-title":"Lymphatic system: A vital link between metabolic syndrome and inflammation","volume":"1207","author":"Chakraborty","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.3389\/fimmu.2019.01036","article-title":"Chronic Liver Disease in Humans Causes Expansion and Differentiation of Liver Lymphatic Endothelial Cells","volume":"10","author":"Tamburini","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1101\/gad.303776.117","article-title":"Lymphangiogenesis guidance by paracrine and pericellular factors","volume":"31","author":"Vaahtomeri","year":"2017","journal-title":"Genes Dev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lee, D., Park, J.S., Kim, D., and Hong, H.S. (2022). Substance P Hinders Bile Acid-Induced Hepatocellular Injury by Modulating Oxidative Stress and Inflammation. Antioxidants, 11.","DOI":"10.3390\/antiox11050920"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3164\/jcbn.13-46","article-title":"The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury","volume":"54","author":"Adachi","year":"2014","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1093\/cvr\/cvaa291","article-title":"The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases","volume":"117","author":"Monaghan","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eabe7359","DOI":"10.1126\/sciadv.abe7359","article-title":"Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance","volume":"7","author":"Ma","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.1242\/jcs.050005","article-title":"Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells","volume":"122","author":"Pan","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1172\/JCI76453","article-title":"Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function","volume":"125","author":"Heo","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1074\/jbc.275.3.1739","article-title":"Reactive Oxygen Species Activate p90 Ribosomal S6 Kinase via Fyn and Ras","volume":"275","author":"Abe","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1053\/j.gastro.2011.02.054","article-title":"Reactive Oxygen Species Induced by Bile Acid Induce Apoptosis and Protect Against Necrosis in Pancreatic Acinar Cells","volume":"140","author":"Booth","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6599","DOI":"10.3748\/wjg.v26.i42.6599","article-title":"Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma","volume":"26","author":"Cho","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e42881","DOI":"10.7554\/eLife.42881","article-title":"Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk","volume":"8","author":"Grimm","year":"2019","journal-title":"Elife"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.celrep.2013.10.030","article-title":"Bile Acids Activate YAP to Promote Liver Carcinogenesis","volume":"5","author":"Anakk","year":"2013","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1002\/hep.28831","article-title":"Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice\u2021","volume":"65","author":"McDaniel","year":"2016","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.ajpath.2019.12.004","article-title":"CXCL11-CXCR3 Axis Mediates Tumor Lymphatic Cross Talk and Inflammation-Induced Tumor, Promoting Pathways in Head and Neck Cancers","volume":"190","author":"Kumaravel","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1002\/hep.27085","article-title":"Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2","volume":"60","author":"Liu","year":"2014","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"30988","DOI":"10.1074\/jbc.M115.668277","article-title":"Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line","volume":"290","author":"Liu","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.ajpath.2018.05.015","article-title":"Conjugated Bile Acids Promote Invasive Growth of Esophageal Adenocarcinoma Cells and Cancer Stem Cell Expansion via Sphingosine 1-Phosphate Receptor 2\u2013Mediated Yes-Associated Protein Activation","volume":"188","author":"Liu","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"C680","DOI":"10.1152\/ajpcell.00122.2015","article-title":"MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation","volume":"309","author":"Chakraborty","year":"2015","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.7150\/ijbs.13851","article-title":"Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: Potential Drug Repurposing for Oral Cancer","volume":"12","author":"Jan","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12492","DOI":"10.1111\/micc.12492","article-title":"Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium","volume":"25","author":"Lee","year":"2018","journal-title":"Microcirculation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e59686","DOI":"10.7554\/eLife.59686","article-title":"Dichotomous role of the human mitochondrial Na+\/Ca2+\/Li+ exchanger NCLX in colorectal cancer growth and metastasis","volume":"9","author":"Pathak","year":"2020","journal-title":"Elife"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.18632\/oncotarget.26660","article-title":"Tumor cells containing the African-Centric S47 variant ofTP53show increased Warburg metabolism","volume":"10","author":"Barnoud","year":"2019","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s13193-020-01210-7","article-title":"Neuropeptide Substance P Enhances Inflammation-Mediated Tumor Signaling Pathways and Migration and Proliferation of Head and Neck Cancers","volume":"12","author":"Singh","year":"2020","journal-title":"Indian J. Surg. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"C1045","DOI":"10.1152\/ajpcell.00299.2020","article-title":"The \u03b21-integrin plays a key role in LEC invasion in an optimized 3-D collagen matrix model","volume":"319","author":"Kumaravel","year":"2020","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-019-5420-z","article-title":"Tumor-associated lymphangiogenesis predicts unfavorable prognosis of intrahepatic cholangiocarcinoma","volume":"19","author":"Sha","year":"2019","journal-title":"BMC Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10456-014-9416-7","article-title":"Inflammation-induced lymphangiogenesis and lymphatic dysfunction","volume":"17","author":"Liao","year":"2014","journal-title":"Angiogenesis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3389\/fmed.2019.00293","article-title":"Inflammation and Progression of Cholangiocarcinoma: Role of Angiogenic and Lymphangiogenic Mechanisms","volume":"6","author":"Roy","year":"2019","journal-title":"Front. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.ajpath.2014.10.013","article-title":"A New Mdr2\u2212\/\u2212 Mouse Model of Sclerosing Cholangitis with Rapid Fibrosis Progression, Early-Onset Portal Hypertension, and Liver Cancer","volume":"185","author":"Ikenaga","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_40","first-page":"1","article-title":"Cholesterol Induces Nrf-2- and HIF-1\u03b1-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis","volume":"2020","author":"Rauchbach","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3727\/105221618X15156018385515","article-title":"Bile Acid Metabolism in Liver Pathobiology","volume":"18","author":"Chiang","year":"2018","journal-title":"Gene Expr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ydbio.2017.12.001","article-title":"How glucose, glutamine and fatty acid metabolism shape blood and lymph vessel development","volume":"447","author":"Teuwen","year":"2019","journal-title":"Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.12688\/f1000research.14803.1","article-title":"Recent advances in understanding lymphangiogenesis and metabolism","volume":"7","author":"Lee","year":"2018","journal-title":"F1000Research"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1093\/carcin\/23.8.1281","article-title":"Bile acids mimic oxidative stress induced upregulation of thioredoxin reductase in colon cancer cell lines","volume":"23","author":"Lechner","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1053\/jhep.2001.22702","article-title":"Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition","volume":"33","author":"Yerushalmi","year":"2001","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.3389\/fchem.2020.592688","article-title":"The Relationship between Reactive Oxygen Species and Endothelial Cell Metabolism","volume":"8","author":"AlHayaza","year":"2020","journal-title":"Front. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1161\/CIRCULATIONAHA.112.116988","article-title":"A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis","volume":"127","author":"Le","year":"2013","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1089\/ars.2015.6556","article-title":"Disturbed Flow-Induced Endothelial Proatherogenic Signaling via Regulating Post-Translational Modifications and Epigenetic Events","volume":"25","author":"Heo","year":"2016","journal-title":"Antioxidants Redox Signal."},{"key":"ref_49","first-page":"1081","article-title":"The post-translational modification, SUMOylation, and cancer (Review)","volume":"52","author":"Han","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"157","DOI":"10.5483\/BMBRep.2018.51.3.016","article-title":"Hippo-YAP\/TAZ signaling in angiogenesis","volume":"51","author":"Park","year":"2018","journal-title":"BMB Rep."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Azad, T., Ghahremani, M., and Yang, X. (2019). The Role of YAP and TAZ in Angiogenesis and Vascular Mimicry. Cells, 8.","DOI":"10.3390\/cells8050407"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"285","DOI":"10.5483\/BMBRep.2021.54.6.020","article-title":"A novel role of Hippo-Yap\/TAZ signaling pathway in lymphatic vascular development","volume":"54","author":"Cha","year":"2021","journal-title":"BMB Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"dev195453","DOI":"10.1242\/dev.195453","article-title":"YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling","volume":"147","author":"Cha","year":"2020","journal-title":"Development"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"017","DOI":"10.1055\/s-0041-1742277","article-title":"Role of YAP1 Signaling in Biliary Development, Repair, and Disease","volume":"42","author":"Molina","year":"2022","journal-title":"Semin. Liver Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101120","DOI":"10.1016\/j.redox.2019.101120","article-title":"Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy","volume":"21","author":"Zhou","year":"2019","journal-title":"Redox Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/hep.1840060650","article-title":"Correspondence","volume":"6","author":"Siciliano","year":"1986","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1021\/pr300337s","article-title":"Urinary Metabolite Variation Is Associated with Pathological Progression of the Post-Hepatitis B Cirrhosis Patients","volume":"11","author":"Wang","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1021\/acs.jproteome.5b00217","article-title":"Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis","volume":"15","author":"Wang","year":"2016","journal-title":"J. Proteome Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1111\/liv.13201","article-title":"Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis","volume":"37","author":"Horvatits","year":"2016","journal-title":"Liver Int."},{"key":"ref_60","first-page":"8079","article-title":"LYVE-1 is not restricted to the lymph vessels: Expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis","volume":"61","author":"Carreira","year":"2001","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/S0002-9440(10)65657-X","article-title":"Morphometric Analysis of Lymphatic and Blood Vessels in Human Chronic Viral Liver Diseases","volume":"153","author":"Yamauchi","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1053\/j.gastro.2005.09.006","article-title":"Microarray Analysis of Endothelial Differentially Expressed Genes in Liver of Cirrhotic Rats","volume":"129","author":"Tugues","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.3389\/fphys.2022.1021038","article-title":"Oxidized low density lipoprotein in the liver causes decreased permeability of liver lymphatic-but not liver sinusoidal-endothelial cells via VEGFR-3 regulation of VE-Cadherin","volume":"13","author":"Goldberg","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Mancinelli, R., Ceci, L., Kennedy, L., Francis, H., Meadows, V., Chen, L., Carpino, G., Kyritsi, K., Wu, N., and Zhou, T. (2022). The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling. Cells, 11.","DOI":"10.3390\/cells11091591"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.bbadis.2017.06.027","article-title":"Animal models of biliary injury and altered bile acid metabolism","volume":"1864","author":"Mariotti","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1002\/hep.25740","article-title":"Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice","volume":"56","author":"Kong","year":"2012","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1002\/hep.20942","article-title":"Conjugated bile acids promote ERK1\/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes","volume":"42","author":"Dent","year":"2005","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1002\/hep.1840400427","article-title":"Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes","volume":"40","author":"Fang","year":"2004","journal-title":"Hepatology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"65","DOI":"10.14715\/cmb\/2020.66.2.10","article-title":"Long-term intervention of taurocholic acid over-expressing in cholestatic liver disease inhibits the growth of hepatoma cells","volume":"66","author":"Zhang","year":"2020","journal-title":"Cell Mol. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1161\/ATVBAHA.108.181610","article-title":"NADPH Oxidases: Functions and Pathologies in the Vasculature","volume":"30","author":"Griendling","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.bcmd.2005.06.010","article-title":"p40phox: The last NADPH oxidase subunit","volume":"35","author":"Matute","year":"2005","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S0014-5793(00)02305-X","article-title":"NADPH oxidase activity is required for endothelial cell proliferation and migration","volume":"486","author":"Abid","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"35544","DOI":"10.1074\/jbc.M608620200","article-title":"A Novel Class of Vascular Endothelial Growth Factor-responsive Genes That Require Forkhead Activity for Expression","volume":"281","author":"Abid","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"35373","DOI":"10.1074\/jbc.M702175200","article-title":"NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways","volume":"282","author":"Abid","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1096\/fj.01-0338fje","article-title":"Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Racl-regulated NADPH oxidase-dependent mechanism","volume":"15","author":"Abid","year":"2001","journal-title":"FASEB J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e21531","DOI":"10.1096\/fj.202002533R","article-title":"Inhibition of NADPH oxidase 4 attenuates lymphangiogenesis and tumor metastasis in breast cancer","volume":"35","author":"Wang","year":"2021","journal-title":"FASEB J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1016\/j.febslet.2008.09.057","article-title":"Modulation of transcriptional corepressor activity of prospero-related homeobox protein (Prox1) by SUMO modification","volume":"582","author":"Shan","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e1700245","DOI":"10.1002\/bies.201700245","article-title":"Endothelial Metabolic Control of Lymphangiogenesis","volume":"40","author":"Yu","year":"2018","journal-title":"Bioessays"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/nature22322","article-title":"FGF-dependent metabolic control of vascular development","volume":"545","author":"Yu","year":"2017","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1146\/annurev-physiol-021115-105134","article-title":"The Link Between Angiogenesis and Endothelial Metabolism","volume":"79","author":"Potente","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"101057","DOI":"10.18632\/oncotarget.22380","article-title":"Bile acid and cigarette smoke enhance the aggressive phenotype of esophageal adenocarcinoma cells by downregulation of the mitochondrial uncoupling protein-2","volume":"8","author":"Xu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-3-030-12668-1_13","article-title":"PFKP Signaling at a Glance: An Emerging Mediator of Cancer Cell Metabolism","volume":"1134","author":"Lang","year":"2019","journal-title":"Rev. Biomark. Stud. Metab. Metab.-Relat. Disord."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Roy, S., Kumaravel, S., Banerjee, P., White, T.K., O\u2019Brien, A., Seelig, C., Chauhan, R., Ekser, B., Bayless, K.J., and Alpini, G. (2021). Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma. Cells, 10.","DOI":"10.3390\/cells10113093"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/labinvest.2016.125","article-title":"Effects of fatty acid synthase inhibitors on lymphatic vessels: An in vitro and in vivo study in a melanoma model","volume":"97","author":"Bastos","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1590\/1678-775720130509","article-title":"FASN expression, angiogenesis and lymphangiogenesis in central and peripheral giant cell lesions","volume":"22","author":"Falci","year":"2014","journal-title":"J. Appl. Oral Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2012.06.037","article-title":"Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling","volume":"150","author":"Yu","year":"2012","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/s41556-018-0142-z","article-title":"YAP\/TAZ upstream signals and downstream responses","volume":"20","author":"Totaro","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1159\/000494790","article-title":"Taurocholate Induces Connective Tissue Growth Factor Expression in Hepatocytes Through ERK-YAP Signaling","volume":"50","author":"Yu","year":"2018","journal-title":"Cell. Physiol. Biochem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/4\/526\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:25:28Z","timestamp":1760120728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/4\/526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,6]]},"references-count":88,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cells12040526"],"URL":"https:\/\/doi.org\/10.3390\/cells12040526","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,6]]}}}