{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:27:11Z","timestamp":1787830031957,"version":"build-2784847793"},"reference-count":79,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["DE027070"],"award-info":[{"award-number":["DE027070"]}]},{"name":"National Institutes of Health","award":["DE030313"],"award-info":[{"award-number":["DE030313"]}]},{"name":"Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs","award":["DE027070"],"award-info":[{"award-number":["DE027070"]}]},{"name":"Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs","award":["DE030313"],"award-info":[{"award-number":["DE030313"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clinical studies have shown that periodontitis is associated with non-alcoholic fatty liver disease (NAFLD). However, it remains unclear if periodontitis contributes to the progression of NAFLD. In this study, we generated a mouse model with high-fat diet (HFD)-induced metabolic syndrome (MetS) and NAFLD and oral P. gingivalis inoculation-induced periodontitis. Results showed that the presence of periodontitis increased insulin resistance and hepatic inflammation and exacerbated the progression of NAFLD. To determine the role of sphingolipid metabolism in the association between NAFLD and periodontitis, we also treated mice with imipramine, an inhibitor of acid sphingomyelinase (ASMase), and demonstrated that imipramine treatment significantly alleviated insulin resistance and hepatic inflammation, and improved NAFLD. Studies performed in vitro showed that lipopolysaccharide (LPS) and palmitic acid (PA), a major saturated fatty acid associated with MetS and NAFLD, synergistically increased the production of ceramide, a bioactive sphingolipid involved in NAFLD progression in macrophages but imipramine effectively reversed the ceramide production stimulated by LPS and PA. Taken together, this study showed for the first time that the presence of periodontitis contributed to the progression of NAFLD, likely due to alterations in sphingolipid metabolism that led to exacerbated insulin resistance and hepatic inflammation. This study also showed that targeting ASMase with imipramine improves NAFLD by reducing insulin resistance and hepatic inflammation.<\/jats:p>","DOI":"10.3390\/ijms24098322","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T03:34:53Z","timestamp":1683516893000},"page":"8322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The Presence of Periodontitis Exacerbates Non-Alcoholic Fatty Liver Disease via Sphingolipid Metabolism-Associated Insulin Resistance and Hepatic Inflammation in Mice with Metabolic Syndrome"],"prefix":"10.3390","volume":"24","author":[{"given":"Zhongyang","family":"Lu","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchun","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8417-909X","authenticated-orcid":false,"given":"Nityananda","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, The James B. Edwards College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0930-6810","authenticated-orcid":false,"given":"Hong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, The James B. Edwards College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing-Kin","family":"Syn","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Saint Louis, MI 63110, USA"},{"name":"Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, Universidad del Pa S Vasco\/Euskal Herriko Univertsitatea (UPV\/EHU), 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lopes-Virella","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3487-7217","authenticated-orcid":false,"given":"\u00d6zlem","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, The James B. Edwards College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1902\/jop.1996.67.10s.1123","article-title":"Periodontal disease and cardiovascular disease","volume":"67","author":"Beck","year":"1996","journal-title":"J. Periodontol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1902\/annals.1996.1.1.821","article-title":"Periodontal diseases: Pathogenesis","volume":"1","author":"Offenbacher","year":"1996","journal-title":"Ann. 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