{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T21:05:34Z","timestamp":1782335134608,"version":"3.54.5"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol. Commun."],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:p>Patients with nonalcoholic fatty liver disease\/steatohepatitis (NAFLD\/NASH) commonly develop atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis, inflammation, oxidative stress, and fibrosis. The role of insulin resistance in their pathogenesis remains controversial. Albumin (<jats:italic toggle=\"yes\">Alb<\/jats:italic>)<jats:italic toggle=\"yes\">Cre+\n                           <\/jats:italic>\n                           <jats:italic toggle=\"yes\">Cc1flox\n                           <\/jats:italic>\n                           <jats:sup>(<\/jats:sup>\n                           <jats:italic toggle=\"yes\">\n                              fl\n                           <\/jats:italic>\n                           <jats:sup>)<\/jats:sup>\n                           <jats:italic toggle=\"yes\">\n                              \/fl\n                           <\/jats:italic> mice with the liver\u2010specific null deletion of the carcinoembryonic antigen\u2010related cell adhesion molecule 1 (<jats:italic toggle=\"yes\">Ceacam1<\/jats:italic>; alias <jats:italic toggle=\"yes\">Cc1<\/jats:italic>) gene display hyperinsulinemia resulting from impaired insulin clearance followed by hepatic insulin resistance, elevated <jats:italic toggle=\"yes\">de novo<\/jats:italic> lipogenesis, and ultimately visceral obesity and systemic insulin resistance. We therefore tested whether this mutation causes NAFLD\/NASH and atherosclerosis. To this end, mice were propagated on a low\u2010density lipoprotein receptor (<jats:italic toggle=\"yes\">Ldlr<\/jats:italic>)<jats:italic toggle=\"yes\">\n                              \u2212\/\u2212\n                           <\/jats:italic> background and at 4\u00a0months of age were fed a high\u2010cholesterol diet for 2\u00a0months. We then assessed the biochemical and histopathologic changes in liver and aortae. <jats:italic toggle=\"yes\">Ldlr\u2212\/\u2212AlbCre+Cc1fl\/fl\n                           <\/jats:italic> mice developed chronic hyperinsulinemia with proatherogenic hypercholesterolemia, a robust proinflammatory state associated with visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue endothelin\u20101 levels. In parallel, they developed NASH (steatohepatitis, apoptosis, and fibrosis) and atherosclerotic plaque lesions. Mechanistically, hyperinsulinemia caused down\u2010regulation of the insulin receptor followed by inactivation of the insulin receptor substrate 1\u2013protein kinase B\u2013endothelial NO synthase pathway in aortae, lowering the NO level. This also limited CEACAM1 phosphorylation and its sequestration of Shc\u2010transforming protein (Shc), activating the Shc\u2013mitogen\u2010activated protein kinase\u2013nuclear factor kappa B pathway and stimulating endothelin\u20101 production. Thus, in the presence of proatherogenic dyslipidemia, hyperinsulinemia and hepatic insulin resistance driven by liver\u2010specific deletion of <jats:italic toggle=\"yes\">Ceacam1<\/jats:italic> caused metabolic and vascular alterations reminiscent of NASH and atherosclerosis. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Altered CEACAM1\u2010dependent hepatic insulin clearance pathways constitute a molecular link between NASH and atherosclerosis.<\/jats:p>","DOI":"10.1002\/hep4.1590","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T17:40:46Z","timestamp":1599154846000},"page":"1591-1609","source":"Crossref","is-referenced-by-count":9,"title":["Loss of Hepatic Carcinoembryonic Antigen\u2010Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis"],"prefix":"10.1097","volume":"4","author":[{"given":"Hilda E.","family":"Ghadieh","sequence":"first","affiliation":[{"name":"Center for Diabetes and Endocrine Research,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"},{"name":"Department of Physiology and Pharmacology,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"},{"name":"Department of Biomedical Sciences,Ohio University,Athens,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghd","family":"Abu Helal","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences,Ohio University,Athens,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrison T.","family":"Muturi","sequence":"additional","affiliation":[{"name":"Center for Diabetes and Endocrine Research,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"},{"name":"Department of Biomedical Sciences,Ohio University,Athens,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella D.","family":"Issa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences,Ohio University,Athens,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Russo","sequence":"additional","affiliation":[{"name":"Center for Diabetes and Endocrine Research,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"},{"name":"Department of Physiology and Pharmacology,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon L.","family":"Abdallah","sequence":"additional","affiliation":[{"name":"Center for Diabetes and Endocrine Research,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"},{"name":"Department of Physiology and Pharmacology,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Najjar","sequence":"additional","affiliation":[{"name":"Center for Diabetes and Endocrine Research,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Benencia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences,Ohio University,Athens,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Center for Diabetes and Endocrine Research,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"},{"name":"Department of Physiology and Pharmacology,University of Toledo College of Medicine and Life Sciences,Toledo,OH,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences,Marshall University Joan C. 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