{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:36:07Z","timestamp":1762432567979,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"Ohio Valley AHA","doi-asserted-by":"publisher","award":["0525318B"],"award-info":[{"award-number":["0525318B"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Pediatrics","award":["0525318B"],"award-info":[{"award-number":["0525318B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity and pediatric fatty liver disease are increasingly prevalent, yet the underlying mechanisms linking these conditions to heightened inflammatory and immune responses remain poorly understood. Using a murine model reflecting early-life obesity and hepatic steatosis, we tested the hypothesis that obesity-driven hepatic inflammation intensifies systemic immune responses and exacerbates vascular dysfunction following innate immune activation. Newly weaned C57BL\/6 mice were fed either a high-saturated-fat, high-cholesterol diet (HFD) or a control diet (CD) for four weeks, modeling adolescence in humans. HFD-fed mice exhibited hepatic and splenic enlargement, elevated plasma cholesterol levels, increased activity levels of liver enzymes (alanine and aspartate aminotransferases), and higher plasma serum amyloid A (SAA) concentrations. Following a sublethal dose of lipopolysaccharide (LPS), the expression of hepatic inflammatory genes (VCAM-1 and iNOS) was significantly elevated in HFD-fed mice, indicating an exaggerated local immune response. Mice fed an HFD also showed significant impairment in endothelium-dependent vasorelaxation compared to CD mice and saline-treated controls, while endothelium-independent responses remained intact. These vascular changes occurred in the context of hepatic inflammation, suggesting that early-life diet-induced steatosis sensitizes the vasculature to inflammatory insult. These findings suggest that obesity-driven hepatic inflammation primes exaggerated systemic immune responses to innate immune stimuli, potentially contributing to the vascular dysfunction and variable clinical morbidity observed in pediatric inflammatory conditions.<\/jats:p>","DOI":"10.3390\/ijms26146802","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T08:24:17Z","timestamp":1752654257000},"page":"6802","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatic Inflammation Primes Vascular Dysfunction Following Treatment with LPS in a Murine Model of Pediatric Fatty Liver Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Hong","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Pediatric Research, Department of Pediatrics, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9972-7677","authenticated-orcid":false,"given":"Robin","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"Division of Pediatric Research, Department of Pediatrics, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5809-7909","authenticated-orcid":false,"given":"Yasir","family":"Alsiraj","sequence":"additional","affiliation":[{"name":"Division of Pediatric Research, Department of Pediatrics, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Murphy","sequence":"additional","affiliation":[{"name":"Division of Pediatric Research, Department of Pediatrics, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Troy E.","family":"Gibbons","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Pediatrics, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Division of Pediatric Research, Department of Pediatrics, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"ref_1","first-page":"2068","article-title":"The Changing Epidemiology of Liver Disease Among US Children and Adolescents From 1999 to 2016","volume":"116","author":"Li","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1080\/17474124.2021.1887730","article-title":"Hepatocyte and immune cell crosstalk in non-alcoholic fatty liver disease","volume":"15","author":"Vetvicka","year":"2021","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s00392-019-01516-9","article-title":"Long- and short-term association of low-grade systemic inflammation with cardiovascular mortality in the LURIC study","volume":"109","author":"Kalsch","year":"2020","journal-title":"Clin. Res. Cardiol."},{"key":"ref_4","first-page":"275","article-title":"The Obesity Paradox in the Pediatric Trauma Patient","volume":"59","author":"Carlson","year":"2024","journal-title":"J. Pediatr. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1007\/s00134-014-3381-x","article-title":"Weight-for-age distribution and case-mix adjusted outcomes of 14,307 paediatric intensive care admissions","volume":"40","author":"Prince","year":"2014","journal-title":"Intensive Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1097\/SHK.0000000000001821","article-title":"The Impact of Obesity on Critical Illnesses","volume":"56","author":"Ayalon","year":"2021","journal-title":"Shock"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.jhep.2021.06.034","article-title":"Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality","volume":"75","author":"Simon","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lyu, X., Liu, B., Li, Y., Wang, Y., Miskovsky, J., Gaitanis, M., Promrat, K., and Wu, W.C. (2024). Impact of Non-Alcoholic Fatty Liver Disease on Sepsis Inpatient Outcomes: A Nationwide Sample Analysis (2000\u20132019). J. Clin. Med., 13.","DOI":"10.21203\/rs.3.rs-4673966\/v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1097\/PEC.0000000000002938","article-title":"Sepsis Prognostic Scores Accuracy in Predicting Adverse Outcomes in Children With Sepsis Admitted to the Pediatric Intensive Care Unit From the Emergency Department: A 10-Year Single-Center Experience","volume":"39","author":"Marchetto","year":"2023","journal-title":"Pediatr. Emerg. Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10689","DOI":"10.1074\/jbc.274.16.10689","article-title":"Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction","volume":"274","author":"Chow","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_11","first-page":"21","article-title":"The role of cytokine mediators in septic shock","volume":"23","author":"Tracey","year":"1990","journal-title":"Adv. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/ajcn\/82.4.751","article-title":"Arterial endothelial dysfunction in baboons fed a high-cholesterol, high-fat diet","volume":"82","author":"Shi","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"H2619","DOI":"10.1152\/ajpheart.00989.2007","article-title":"CD4+ T lymphocytes mediate hypercholesterolemia-induced endothelial dysfunction via a NAD(P)H oxidase-dependent mechanism","volume":"294","author":"Wolfort","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Shah, P., Petersen, T.L., Zhang, L., Yan, K., and Thompson, N.E. (2022). Using Aggregate Vasoactive-Inotrope Scores to Predict Clinical Outcomes in Pediatric Sepsis. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.778378"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: Relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1476-9255-4-22","article-title":"Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet","volume":"4","author":"Huang","year":"2007","journal-title":"J. Inflamm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.gene.2004.06.015","article-title":"Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model","volume":"340","author":"Kim","year":"2004","journal-title":"Gene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"42774","DOI":"10.1074\/jbc.M306022200","article-title":"Cholesterol and cholate components of an atherogenic diet induce distinct stages of hepatic inflammatory gene expression","volume":"278","author":"Vergnes","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Vinue, A., Herrero-Cervera, A., and Gonzalez-Navarro, H. (2018). Understanding the Impact of Dietary Cholesterol on Chronic Metabolic Diseases through Studies in Rodent Models. Nutrients, 10.","DOI":"10.3390\/nu10070939"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0002-9343(80)90178-3","article-title":"Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy","volume":"68","author":"Wilson","year":"1980","journal-title":"Am. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1542\/peds.2005-2992","article-title":"Pediatric precursors of adult cardiovascular disease: Noninvasive assessment of early vascular changes in children and adolescents","volume":"118","author":"Groner","year":"2006","journal-title":"Pediatrics"},{"key":"ref_22","unstructured":"Bruzzi, P., Predieri, B., Madeo, S., Lami, F., and Iughetti, L. (2021). Longitudinal evaluation of endothelial markers in children and adolescents with familial hypercholesterolemia. Acta Biomed., 92."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Faraj, T.A., Stover, C., and Erridge, C. (2019). Dietary Toll-Like Receptor Stimulants Promote Hepatic Inflammation and Impair Reverse Cholesterol Transport in Mice via Macrophage-Dependent Interleukin-1 Production. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01404"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1161\/CIRCRESAHA.106.142851","article-title":"Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity","volume":"100","author":"Kim","year":"2007","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s000110050579","article-title":"Endothelium function in sepsis","volume":"49","author":"Volk","year":"2000","journal-title":"Inflamm. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jpeds.2013.08.069","article-title":"Non-high-density lipoprotein cholesterol: Distribution and prevalence of high serum levels in children and adolescents: United States National Health and Nutrition Examination Surveys, 2005\u20132010","volume":"164","author":"Dai","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1001\/jama.2012.9136","article-title":"Trends in serum lipids among US youths aged 6 to 19 years, 1988\u20132010","volume":"308","author":"Kit","year":"2012","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1093\/ajcp\/34.4_ts.381","article-title":"Revised spectrophotometric methods for the determination of glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, and lactic acid dehydrogenase","volume":"34","author":"Henry","year":"1960","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1096\/fasebj.14.2.271","article-title":"Endothelial dysfunction and peroxynitrite formation are early events in angiotensin-induced cardiovascular disorders","volume":"14","author":"Wattanapitayakul","year":"2000","journal-title":"FASEB J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6802\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:10:24Z","timestamp":1760033424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6802"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":29,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146802"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146802","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,7,16]]}}}