{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:53:55Z","timestamp":1779206035604,"version":"3.51.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T00:00:00Z","timestamp":1732320000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T00:00:00Z","timestamp":1732320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82200881"],"award-info":[{"award-number":["82200881"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82200920"],"award-info":[{"award-number":["82200920"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Clinical Medical 5010 Project Foundation of Sun Yat-sen University","award":["2017001"],"award-info":[{"award-number":["2017001"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Diabetes, a global epidemic, is the leading cause of mortality globally. The aim of this study is to get better understanding of pathophysiology of diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Palmitic acid (PA)-treated \u03b2-cells, db\/db mice and high fat diet (HFD)-fed mouse model of type 2 diabetes were established. H&amp;E was used to assess the histological changes of pancreas. IHC, FISH, western blot or qRT-PCR was employed to detect the expression of key molecules in primary islets or lipotoxic \u03b2-cells. Cell behaviors were detected by MTT, EdU incorporation assay, TUNEL assay and glucose-induced insulin secretion (GSIS). The associations among circMlxipl, Mbnl1 and Rbbp6 were validated by RIP and RNA pull-down assays, and the direct binding between Hdac3 and Mbnl1 promoter was examined by ChIP and luciferase assays. Co-IP was employed to assess the interaction between ChREBP and Rbbp6, as well as the ubiquitination of ChREBP.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Hdac3 and ChREBP were upregulated, but Mbnl1 and circMlxipl were downregulated in islets from diabetic mice and lipotoxic \u03b2-cells. Mbnl1 overexpression protected against PA-induced impairments in lipotoxic \u03b2-cells through modulating back-splicing of circMlxipl and suppressing ChREBP. Hdac3 served as a transcriptional repressor of Mbnl1, and it was implicated in circMlxipl-mediated protection via regulating ChREBP expression in lipotoxic \u03b2-cells. Lack of circMlxipl inhibited Rbbp6-mediated ubiquitin-proteasomal degradation of ChREBP in lipotoxic \u03b2-cells. In vivo studies revealed that Hdac3 knockdown or Mbnl1 overexpression alleviated diabetes symptoms through circMlxipl-regulated ChREBP in diabetic mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Mbnl1-mediated alternative splicing of circMlxipl regulates Rbbp6-involved ChREBP turnover to inhibit lipotoxicity-induced \u03b2-cell damage.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10020-024-00991-9","type":"journal-article","created":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T09:08:37Z","timestamp":1732352917000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mbnl1-mediated alternative splicing of circMlxipl regulates Rbbp6-involved ChREBP turnover to inhibit lipotoxicity-induced \u03b2-cell damage"],"prefix":"10.1186","volume":"30","author":[{"given":"Yingying","family":"Gong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meilin","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaopei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changliu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiewen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Pei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanbing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haipeng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liting","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,23]]},"reference":[{"key":"991_CR1","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/j.jmb.2008.09.060","volume":"384","author":"M Chibi","year":"2008","unstructured":"Chibi M, et al. RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1. J Mol Biol. 2008;384:908\u201316.","journal-title":"J Mol Biol"},{"key":"991_CR2","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.chembiol.2012.05.010","volume":"19","author":"DH Chou","year":"2012","unstructured":"Chou DH, et al. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol. 2012;19:669\u201373.","journal-title":"Chem Biol"},{"key":"991_CR3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s12575-021-00143-x","volume":"23","author":"KL Corbin","year":"2021","unstructured":"Corbin KL, et al. A practical guide to rodent islet isolation and assessment revisited. Biol Proced Online. 2021;23:7.","journal-title":"Biol Proced Online"},{"key":"991_CR4","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.jcjd.2020.08.001","volume":"44","author":"Diabetes Canada Clinical Practice Guidelines Expert C","year":"2020","unstructured":"Diabetes Canada Clinical Practice Guidelines Expert C, et al. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update. Can J Diabetes. 2020;44:575\u201391.","journal-title":"Can J Diabetes"},{"key":"991_CR5","doi-asserted-by":"publisher","first-page":"130","DOI":"10.4239\/wjd.v14.i3.130","volume":"14","author":"PV Dludla","year":"2023","unstructured":"Dludla PV, et al. Pancreatic beta-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes. 2023;14:130\u201346.","journal-title":"World J Diabetes"},{"key":"991_CR6","doi-asserted-by":"publisher","first-page":"6275","DOI":"10.3390\/ijms21176275","volume":"21","author":"U Galicia-Garcia","year":"2020","unstructured":"Galicia-Garcia U, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21:6275.","journal-title":"Int J Mol Sci"},{"key":"991_CR7","doi-asserted-by":"publisher","first-page":"19601","DOI":"10.1007\/s11356-021-12781-5","volume":"28","author":"A Gupta","year":"2021","unstructured":"Gupta A, et al. Role of UPP pathway in amelioration of diabetes-associated complications. Environ Sci Pollut Res Int. 2021;28:19601\u201314.","journal-title":"Environ Sci Pollut Res Int"},{"key":"991_CR8","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nature10986","volume":"484","author":"MA Herman","year":"2012","unstructured":"Herman MA, et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature. 2012;484:333\u20138.","journal-title":"Nature"},{"key":"991_CR9","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.7150\/thno.42174","volume":"10","author":"A Huang","year":"2020","unstructured":"Huang A, Zheng H, Wu Z, Chen M, Huang Y. Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics. 2020;10:3503\u201317.","journal-title":"Theranostics"},{"key":"991_CR10","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12964-020-00681-z","volume":"19","author":"S Huang","year":"2021","unstructured":"Huang S, et al. Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2. Cell Commun Signal. 2021;19:35.","journal-title":"Cell Commun Signal"},{"key":"991_CR11","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/s42255-022-00618-5","volume":"4","author":"C Jain","year":"2022","unstructured":"Jain C, Ansarullah BS, Lickert H. Targeting pancreatic beta cells for diabetes treatment. Nat Metab. 2022;4:1097\u2013108.","journal-title":"Nat Metab"},{"key":"991_CR12","doi-asserted-by":"publisher","first-page":"8708236","DOI":"10.1155\/2020\/8708236","volume":"2020","author":"X Jiang","year":"2020","unstructured":"Jiang X, et al. Metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1\/miR-130a-3p\/STAT3 pathway. Oxid Med Cell Longev. 2020;2020:8708236.","journal-title":"Oxid Med Cell Longev"},{"key":"991_CR13","doi-asserted-by":"publisher","first-page":"7507","DOI":"10.7150\/thno.59546","volume":"11","author":"C Jiaxin","year":"2021","unstructured":"Jiaxin C, et al. Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer. Theranostics. 2021;11:7507\u201326.","journal-title":"Theranostics"},{"key":"991_CR14","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/j.molmet.2016.09.010","volume":"5","author":"G Jing","year":"2016","unstructured":"Jing G, Chen J, Xu G, Shalev A. Islet ChREBP-beta is increased in diabetes and controls ChREBP-alpha and glucose-induced gene expression via a negative feedback loop. Mol Metab. 2016;5:1208\u201315.","journal-title":"Mol Metab"},{"key":"991_CR15","doi-asserted-by":"publisher","first-page":"4423","DOI":"10.1038\/s41467-022-32162-x","volume":"13","author":"LS Katz","year":"2022","unstructured":"Katz LS, et al. Maladaptive positive feedback production of ChREBPbeta underlies glucotoxic beta-cell failure. Nat Commun. 2022;13:4423.","journal-title":"Nat Commun"},{"key":"991_CR16","doi-asserted-by":"publisher","first-page":"7951","DOI":"10.1073\/pnas.0701916104","volume":"104","author":"L Li","year":"2007","unstructured":"Li L, et al. PACT is a negative regulator of p53 and essential for cell growth and embryonic development. Proc Natl Acad Sci U S A. 2007;104:7951\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"991_CR17","doi-asserted-by":"publisher","first-page":"31222","DOI":"10.1038\/srep31222","volume":"6","author":"P Malakar","year":"2016","unstructured":"Malakar P, et al. Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival. Sci Rep. 2016;6:31222.","journal-title":"Sci Rep"},{"key":"991_CR18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.2217\/epi.14.11","volume":"6","author":"BC Meier","year":"2014","unstructured":"Meier BC, Wagner BK. Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. Epigenomics. 2014;6:209\u201314.","journal-title":"Epigenomics"},{"key":"991_CR19","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.imbio.2014.03.002","volume":"219","author":"P Moela","year":"2014","unstructured":"Moela P, Choene MM, Motadi LR. Silencing RBBP6 (Retinoblastoma Binding Protein 6) sensitises breast cancer cells MCF7 to staurosporine and camptothecin-induced cell death. Immunobiology. 2014;219:593\u2013601.","journal-title":"Immunobiology"},{"key":"991_CR20","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/j.imbio.2011.05.004","volume":"216","author":"LR Motadi","year":"2011","unstructured":"Motadi LR, Bhoola KD, Dlamini Z. Expression and function of retinoblastoma binding protein 6 (RBBP6) in human lung cancer. Immunobiology. 2011;216:1065\u201373.","journal-title":"Immunobiology"},{"key":"991_CR21","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/S2213-8587(21)00113-3","volume":"9","author":"MA Nauck","year":"2021","unstructured":"Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol. 2021;9:525\u201344.","journal-title":"Lancet Diabetes Endocrinol"},{"key":"991_CR22","doi-asserted-by":"publisher","first-page":"29280295","DOI":"10.1002\/wrna.1459","volume":"9","author":"CA Nutter","year":"2018","unstructured":"Nutter CA, Kuyumcu-Martinez MN. Emerging roles of RNA-binding proteins in diabetes and their therapeutic potential in diabetic complications. Wiley Interdiscip Rev RNA. 2018;9:29280295.","journal-title":"Wiley Interdiscip Rev RNA"},{"key":"991_CR23","doi-asserted-by":"publisher","first-page":"195739","DOI":"10.1155\/2014\/195739","volume":"2014","author":"V Plaisance","year":"2014","unstructured":"Plaisance V, et al. The class I histone deacetylase inhibitor MS-275 prevents pancreatic beta cell death induced by palmitate. J Diabetes Res. 2014;2014:195739.","journal-title":"J Diabetes Res"},{"key":"991_CR24","doi-asserted-by":"publisher","first-page":"2710","DOI":"10.2337\/db11-0132","volume":"60","author":"CA Robson-Doucette","year":"2011","unstructured":"Robson-Doucette CA, et al. Beta-cell uncoupling protein 2 regulates reactive oxygen species production, which influences both insulin and glucagon secretion. Diabetes. 2011;60:2710\u20139.","journal-title":"Diabetes"},{"key":"991_CR25","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1055\/a-1624-2897","volume":"130","author":"E Schleicher","year":"2022","unstructured":"Schleicher E, et al. Definition, classification and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes. 2022;130:S1\u20138.","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"991_CR26","doi-asserted-by":"publisher","first-page":"25426","DOI":"10.1074\/jbc.M109.095224","volume":"285","author":"S Sen","year":"2010","unstructured":"Sen S, et al. Muscleblind-like 1 (Mbnl1) promotes insulin receptor exon 11 inclusion via binding to a downstream evolutionarily conserved intronic enhancer. J Biol Chem. 2010;285:25426\u201337.","journal-title":"J Biol Chem"},{"key":"991_CR27","doi-asserted-by":"publisher","first-page":"3328","DOI":"10.3390\/cells10123328","volume":"10","author":"EA Vilas-Boas","year":"2021","unstructured":"Vilas-Boas EA, Almeida DC, Roma LP, Ortis F, Carpinelli AR. Lipotoxicity and beta-cell failure in type 2 diabetes: oxidative stress linked to NADPH oxidase and ER stress. Cells. 2021;10:3328.","journal-title":"Cells"},{"key":"991_CR28","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1530\/JME-20-0079","volume":"65","author":"L Wu","year":"2020","unstructured":"Wu L, et al. Circ-Tulp4 promotes beta-cell adaptation to lipotoxicity by regulating soat1 expression. J Mol Endocrinol. 2020;65:149\u201361.","journal-title":"J Mol Endocrinol"},{"key":"991_CR29","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s43556-021-00043-2","volume":"2","author":"Q Yang","year":"2021","unstructured":"Yang Q, Zhao J, Chen D, Wang Y. E3 ubiquitin ligases: styles, structures and functions. Mol Biomed. 2021;2:23.","journal-title":"Mol Biomed"},{"key":"991_CR30","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11892-024-01533-7","volume":"24","author":"G Yu","year":"2024","unstructured":"Yu G, et al. Lessons and applications of omics research in diabetes epidemiology. Curr Diab Rep. 2024;24:27\u201344.","journal-title":"Curr Diab Rep"},{"key":"991_CR31","doi-asserted-by":"publisher","first-page":"4158","DOI":"10.2337\/db15-0239","volume":"64","author":"P Zhang","year":"2015","unstructured":"Zhang P, et al. Induction of the ChREBPbeta isoform is essential for glucose-stimulated beta-cell proliferation. Diabetes. 2015;64:4158\u201370.","journal-title":"Diabetes"},{"key":"991_CR32","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1101\/gr.202895.115","volume":"26","author":"XO Zhang","year":"2016","unstructured":"Zhang XO, et al. Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res. 2016;26:1277\u201387.","journal-title":"Genome Res"},{"key":"991_CR33","doi-asserted-by":"publisher","first-page":"953880","DOI":"10.3389\/fphys.2022.953880","volume":"13","author":"S Zhang","year":"2022","unstructured":"Zhang S, et al. Post-transcriptional control by RNA-binding proteins in diabetes and its related complications. Front Physiol. 2022;13:953880.","journal-title":"Front Physiol"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-024-00991-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-024-00991-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-024-00991-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T22:02:32Z","timestamp":1732399352000},"score":1,"resource":{"primary":{"URL":"https:\/\/molmed.biomedcentral.com\/articles\/10.1186\/s10020-024-00991-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,23]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["991"],"URL":"https:\/\/doi.org\/10.1186\/s10020-024-00991-9","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,23]]},"assertion":[{"value":"20 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal studies were approved by the committee for Clinical Research and Animal Trials of the First Affiliated Hospital of Sun Yat-sen University (Research Protocol [2017]056).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"229"}}