{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T14:32:56Z","timestamp":1778077976651,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"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":["32272893"],"award-info":[{"award-number":["32272893"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","award":["2021ZDZX0009"],"award-info":[{"award-number":["2021ZDZX0009"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013314","name":"111 Project","doi-asserted-by":"crossref","award":["D17015"],"award-info":[{"award-number":["D17015"]}],"id":[{"id":"10.13039\/501100013314","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Long-term nutritional excess causes hepatic steatosis, endoplasmic reticulum (ER) stress, hyperglycemia, and hyperlipidemia. Mitogen-activated protein kinase phosphatase-3 (MKP-3) is a well-established stress-regulated protein and a regulator of gluconeogenesis. Our previous study revealed that acute ER stress reduced gluconeogenesis and MKP-3 protein stability. However, the expression of MKP-3 and its regulatory mechanisms in chronic ER stress remain unclear. The aim of this study was to investigate the effects of chronic ER stress on hepatic MKP-3 expression and its role in the regulation of gluconeogenesis. The results show that long-term administration of thapsigargin (Tg) or palmitic acid promoted gene expression of Mkp-3 and gluconeogenic genes Pepck, G6pc, and Pgc1\u03b1 in primary mouse hepatocytes. In addition, a long-term high-fat diet (HFD) or Tg administration significantly increased hepatic ER stress and blood glucose level in mice, while inducing the expression of Mkp-3 and hepatic gluconeogenic genes Pepck, G6pc and Pgc1\u03b1. Further study revealed that liver-specific Mkp-3 knockout (Mkp-3 LKO) reversed the blood glucose level and expression levels of gluconeogenic genes those were induced by long-term HFD in mice. Moreover, activation of the PKR-like ER kinase (PERK) by its agonist increased hepatic Mkp-3 expression, whereas inhibitor of PERK suppressed the expression of Mkp-3 under Tg administration. These results suggest that chronic high-fat diet might promote hepatic gluconeogenesis via the PERK\/MKP-3 pathway. Consequently, this study identified a potential therapeutic target for treating obesity-related hyperglycemia.<\/jats:p>","DOI":"10.3390\/ijms27062874","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"2874","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MAPK Phosphatase-3 Mediates Chronic Endoplasmic Reticulum Stress Promoting Hepatic Gluconeogenesis"],"prefix":"10.3390","volume":"27","author":[{"given":"Sheng","family":"Cao","sequence":"first","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"Animal Nutrition and Feed Efficient Utilization Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanlin","family":"Du","sequence":"additional","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengfeng","family":"Fang","sequence":"additional","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"College of Food Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianqiang","family":"Che","sequence":"additional","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6816-5192","authenticated-orcid":false,"given":"Lun","family":"Hua","sequence":"additional","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengmeng","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"De","family":"Wu","sequence":"additional","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6258-2729","authenticated-orcid":false,"given":"Bin","family":"Feng","sequence":"additional","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"Key Laboratory of Animal Disease-Resistant Nutrition of Ministry of Education, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, China"},{"name":"Animal Nutrition and Feed Efficient Utilization Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu 611130, 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