{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T14:59:41Z","timestamp":1792162781422,"version":"4.4.0"},"reference-count":35,"publisher":"Frontiers Media SA","issue":"6","license":[{"start":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T00:00:00Z","timestamp":1607558400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"National Program on Key Basic Research Project","award":["2015CB964702, 2015CB964601"],"award-info":[{"award-number":["2015CB964702, 2015CB964601"]}]},{"name":"Experimental Animal Research Fund, and Science and Technology Commission of Shanghai Municipality","award":["15140903900"],"award-info":[{"award-number":["15140903900"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570521, Key Program 81430026"],"award-info":[{"award-number":["81570521, Key Program 81430026"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Exp Biol Med (Maywood)"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:p>\n                    Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening human health, yet no medicine is developed to treat this disease. In this study, we first discovered that Leptin mutant rats ( Lep\n                    <jats:sup>\u0394I14\/\u0394I14<\/jats:sup>\n                    ) exhibit characteristic NASH phenotypes including steatosis, lymphocyte infiltration, and ballooning after postnatal week 16. We then examined NASH progression by performing an integrated analysis of hepatic transcriptome in Leptin-deficient rats from postnatal 4 to 48\u2009weeks. Initially, simple steatosis in Lep\n                    <jats:sup>\u0394I14\/\u0394I14<\/jats:sup>\n                    rats were observed with increased expression of the genes encoding for rate-limiting enzymes in lipid metabolism such as acetyl-CoA carboxylase and fatty acid synthase. When NASH phenotypes became well developed at postnatal week 16, we found gene expression changes in insulin resistance, inflammation, reactive oxygen species and endoplasmic reticulum stress. As NASH phenotypes further progressed with age, we observed elevated expression of cytokines and chemokines including C-C motif chemokine ligand 2, tumor necrosis factor \u0251, interleukin-6, and interleukin-1\u03b2 together with activation of the c-Jun N-terminal kinase and nuclear factor-\u03baB pathways. Histologically, livers in Lep\n                    <jats:sup>\u0394I14\/\u0394I14<\/jats:sup>\n                    rats exhibited increased cell infiltration of MPO\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils, CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, CD68\n                    <jats:sup>+<\/jats:sup>\n                    hepatic macrophages, and CCR2\n                    <jats:sup>+<\/jats:sup>\n                    inflammatory monocyte-derived macrophages associated with macrophage polarization from M2 to M1. Subsequent cross-species comparison of transcriptomes in human, rat, and mouse NASH models indicated that Leptin-deficient rats bear more similarities to human NASH patients than previously established mouse NASH models. Taken together, our study suggests that Lep\n                    <jats:sup>\u0394I14\/\u0394I14<\/jats:sup>\n                    rats are a valuable pre-clinical rodent model to evaluate NASH drug safety and efficacy.\n                  <\/jats:p>","DOI":"10.1177\/1535370220976530","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:32:46Z","timestamp":1607646766000},"page":"678-687","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["Characterizing disease progression of nonalcoholic steatohepatitis in\n                    <i>Leptin<\/i>\n                    -deficient rats by integrated transcriptome analysis"],"prefix":"10.3389","volume":"246","author":[{"given":"Ping","family":"Lu","sequence":"first","affiliation":[{"name":"Tongji Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200092, China"},{"name":"Translational Center for Stem Cell 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