{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T14:31:12Z","timestamp":1792161072060,"version":"4.4.0"},"reference-count":42,"publisher":"American Diabetes Association","issue":"12","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,12,1]]},"abstract":"<jats:p>OBJECTIVE\u2014Regulation of phosphoenolpyruvate carboxykinase (PEPCK), the key gene in gluconeogenesis, is critical for glucose homeostasis in response to quick nutritional depletion and\/or hormonal alteration.<\/jats:p>\n               <jats:p>RESEARCH DESIGN\/METHODS AND RESULTS\u2014 Here, we identified the testicular orphan nuclear receptor 4 (TR4) as a key PEPCK regulator modulating PEPCK gene via a transcriptional mechanism. TR4 transactivates the 490-bp PEPCK promoter-containing luciferase reporter gene activity by direct binding to the TR4 responsive element (TR4RE) located at \u2212451 to \u2212439 in the promoter region. Binding to TR4RE was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Eliminating TR4 via knockout and RNA interference (RNAi) in hepatocytes significantly reduced the PEPCK gene expression and glucose production in response to glucose depletion. In contrast, ectopic expression of TR4 increased PEPCK gene expression and hepatic glucose production in human and mouse hepatoma cells. Mice lacking TR4 also display reduction of PEPCK expression with impaired gluconeogenesis.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014Together, both in vitro and in vivo data demonstrate the identification of a new pathway, TR4 \u2192 PEPCK \u2192 gluconeogenesis \u2192 blood glucose, which may allow us to modulate metabolic programs via the control of a new key player, TR4, a member of the nuclear receptor superfamily.<\/jats:p>","DOI":"10.2337\/db07-0359","type":"journal-article","created":{"date-parts":[[2007,9,8]],"date-time":"2007-09-08T00:54:09Z","timestamp":1189212849000},"page":"2901-2909","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":67,"title":["Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase\u2013Mediated Gluconeogenesis"],"prefix":"10.2337","volume":"56","author":[{"given":"Ning-Chun","family":"Liu","sequence":"first","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Jye","family":"Lin","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eungseok","family":"Kim","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"},{"name":"Department of Biological Sciences, Chonnam National University, Gwangju, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loretta L.","family":"Collins","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Yun","family":"Lin","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Chen","family":"Yu","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet D.","family":"Sparks","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Min","family":"Chen","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"},{"name":"Department of Obstetrics and Gynecology, China Medical University\/Hospital, Taichung, Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Fen","family":"Lee","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chawnshang","family":"Chang","sequence":"additional","affiliation":[{"name":"George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031207511660000_R1","doi-asserted-by":"crossref","unstructured":"Hanson RW, Reshef L: Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. 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