{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:06:35Z","timestamp":1779199595412,"version":"3.51.4"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T00:00:00Z","timestamp":1696464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17SFRN33560006"],"award-info":[{"award-number":["17SFRN33560006"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17SFRN33610014"],"award-info":[{"award-number":["17SFRN33610014"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20SFRN35210662"],"award-info":[{"award-number":["20SFRN35210662"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA\u2010induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA\u2010induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA\u2010induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA\u2010induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N\u2010acetyl cysteine (NAC) significantly attenuated the FFA\u2010induced reduction of IPMK and restored FFA\u2010induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA\u2010induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.<\/jats:p>","DOI":"10.1002\/jcb.30478","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T19:47:08Z","timestamp":1696535228000},"page":"1695-1704","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Inositol polyphosphate multikinase modulates free fatty acids\u2010induced insulin resistance in primary mouse hepatocytes"],"prefix":"10.1002","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7541-2251","authenticated-orcid":false,"given":"Ik\u2010Rak","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology Diabetes and Metabolism, Johns Hopkins University Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rexford S.","family":"Ahima","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology Diabetes and Metabolism, Johns Hopkins University Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangwon F.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology Diabetes and Metabolism, Johns Hopkins University Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,10,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119751109"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.01.007"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2014.02.003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.12.3458"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI123069"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-12-0214"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygcen.2017.01.018"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001254"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902380106"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2010.11.006"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M901488200"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30827"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017831108"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(01)00056-4"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.1.330-337.2004"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2022.00067"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bj.2017.06.007"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311401"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2016.05.001"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.01.011"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1525-1381.1999.99220.x"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13449"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1530\/EC-21-0248"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0410-400"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611550200"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00577"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0015"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.4239\/wjd.v6.i3.456"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.03.059"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.03.011"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106623"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13020332"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.042663"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.03.034"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10010036"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191313"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2014.03.017"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-511X-12-104"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2014.12.009"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05310-w"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127374"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2017.11.009"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3565"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2013.01.015"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-010-0646-8"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep37468"}],"container-title":["Journal of Cellular Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcb.30478","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T23:56:33Z","timestamp":1700783793000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcb.30478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,5]]},"references-count":46,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/jcb.30478"],"URL":"https:\/\/doi.org\/10.1002\/jcb.30478","archive":["Portico"],"relation":{},"ISSN":["0730-2312","1097-4644"],"issn-type":[{"value":"0730-2312","type":"print"},{"value":"1097-4644","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,5]]},"assertion":[{"value":"2023-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}