{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:43:13Z","timestamp":1787067793433,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82104655"],"award-info":[{"award-number":["82104655"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021046"],"award-info":[{"award-number":["2021046"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["0362022012"],"award-info":[{"award-number":["0362022012"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Science and Technology Department of Sichuan Province Seedling Engineering","award":["82104655"],"award-info":[{"award-number":["82104655"]}]},{"name":"the Science and Technology Department of Sichuan Province Seedling Engineering","award":["2021046"],"award-info":[{"award-number":["2021046"]}]},{"name":"the Science and Technology Department of Sichuan Province Seedling Engineering","award":["0362022012"],"award-info":[{"award-number":["0362022012"]}]},{"name":"the Special Foundation for Inheritance and Innovation in School of Basic Medical Sciences of CDUTCM","award":["82104655"],"award-info":[{"award-number":["82104655"]}]},{"name":"the Special Foundation for Inheritance and Innovation in School of Basic Medical Sciences of CDUTCM","award":["2021046"],"award-info":[{"award-number":["2021046"]}]},{"name":"the Special Foundation for Inheritance and Innovation in School of Basic Medical Sciences of CDUTCM","award":["0362022012"],"award-info":[{"award-number":["0362022012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Non-alcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to other severe liver diseases, yet treatment options are limited. Endoplasmic reticulum (ER) stress is an important pathogenetic mechanism of NASH and plays a key role in tandem steatosis as well as liver inflammation. This study aims to develop a progressive NASH model through sustained lipid accumulation and to elucidate its molecular mechanism through IRE1\u03b1\/TRAF2 complex. Male SD rats were fed a high-fat diet (HFD) for 4, 8, and 12 weeks to induce progressive NASH. MRNA sequencing and PPI analysis were used to screen core genes. Transmission electron microscopy, immunofluorescence staining, ELISA, qRT-PCR, and Western blotting were used at each time point to compare differences between each index of progressive NASH at 4, 8, and 12 weeks. Sustained lipid accumulation led to structural disruption of the ER, a reduction in ER number, and an increase of lipid droplet aggregation in hepatocytes. Persistent lipid accumulation led to a persistent increase in mRNA and protein expression of the IRE1\u03b1\/TRAF2 complex, IKK\/I\u03baB\/NF-\u03baB signaling pathway and ASK1\/JNK1 signaling pathway, and TNF-\u03b1, IL-1\u03b2, and IL-6 also continued to increase. Persistent lipid accumulation led to a persistent exacerbation of ER stress and inflammation in progressive NASH via the IRE1\u03b1\/TRAF2 complex.<\/jats:p>","DOI":"10.3390\/molecules28073185","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T02:03:00Z","timestamp":1680573780000},"page":"3185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Persistent Lipid Accumulation Leads to Persistent Exacerbation of Endoplasmic Reticulum Stress and Inflammation in Progressive NASH via the IRE1\u03b1\/TRAF2 Complex"],"prefix":"10.3390","volume":"28","author":[{"given":"Na","family":"Lei","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3994-9419","authenticated-orcid":false,"given":"Hongfei","family":"Song","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zeng","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxiu","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbo","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuying","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quansheng","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jibin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Mu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/liv.14362","article-title":"Natural history of NASH and HCC","volume":"40","author":"Negro","year":"2020","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/hep4.1479","article-title":"Pathogenesis of nonalcoholic steatohepatitis: An overview","volume":"4","author":"Parthasarathy","year":"2020","journal-title":"Hepatol. 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