PDK4 Deficiency Suppresses Hepatic Glucagon Signaling by Decreasing cAMP Levels
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Park, Bo-Yoon | - |
dc.contributor.author | Jeon, Jae-Han | - |
dc.contributor.author | Go, Younghoon | - |
dc.contributor.author | Ham, Hye Jin | - |
dc.contributor.author | Kim, Jeong-Eun | - |
dc.contributor.author | Yoo, Eun Kyung | - |
dc.contributor.author | Kwon, Woong Hee | - |
dc.contributor.author | Jeoung, Nam-Ho | - |
dc.contributor.author | Jeon, Yong Hyun | - |
dc.contributor.author | Koo, Seung-Hoi | - |
dc.contributor.author | Kim, Byung-Gyu | - |
dc.contributor.author | He, Ling | - |
dc.contributor.author | Park, Keun-Gyu | - |
dc.contributor.author | Harris, Robert A. | - |
dc.contributor.author | Lee, In-Kyu | - |
dc.date.accessioned | 2021-09-02T05:24:16Z | - |
dc.date.available | 2021-09-02T05:24:16Z | - |
dc.date.created | 2021-06-19 | - |
dc.date.issued | 2018-10 | - |
dc.identifier.issn | 0012-1797 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/72578 | - |
dc.description.abstract | In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)-CREB signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation, which limits the availability of gluconeogenic substrates in the liver. However, this study found upregulation of hepatic PDK4 promoted glucagon-mediated expression of gluconeogenic genes, whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production. Mechanistically, PDK4 deficiency decreased ATP levels, thus increasing phosphorylated AMPK (p-AMPK), which increased p-AMPK-sensitive phosphorylation of cyclic nucleotide phosphodiesterase 4B (p-PDE4B). This reduced cAMP levels and consequently p-CREB. Metabolic flux analysis showed that the reduction in ATP was a consequence of a diminished rate of fatty acid oxidation (FAO). However, overexpression of PDK4 increased FAO and increased ATP levels, which decreased p-AMPK and p-PDE4B and allowed greater accumulation of cAMP and p-CREB. The latter were abrogated by the FAO inhibitor etomoxir, suggesting a critical role for PDK4 in FAO stimulation and the regulation of cAMP levels. This finding strengthens the possibility of PDK4 as a target against diabetes. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | AMER DIABETES ASSOC | - |
dc.subject | PYRUVATE-DEHYDROGENASE COMPLEX | - |
dc.subject | TRANSCRIPTION FACTOR | - |
dc.subject | INDUCED ACTIVATION | - |
dc.subject | LEYDIG-CELLS | - |
dc.subject | CYCLIC-AMP | - |
dc.subject | GLUCONEOGENESIS | - |
dc.subject | GLUCOSE | - |
dc.subject | METABOLISM | - |
dc.subject | CREB | - |
dc.subject | PHOSPHORYLATION | - |
dc.title | PDK4 Deficiency Suppresses Hepatic Glucagon Signaling by Decreasing cAMP Levels | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Koo, Seung-Hoi | - |
dc.identifier.doi | 10.2337/db17-1529 | - |
dc.identifier.scopusid | 2-s2.0-85054779774 | - |
dc.identifier.wosid | 000445059100013 | - |
dc.identifier.bibliographicCitation | DIABETES, v.67, no.10, pp.2054 - 2068 | - |
dc.relation.isPartOf | DIABETES | - |
dc.citation.title | DIABETES | - |
dc.citation.volume | 67 | - |
dc.citation.number | 10 | - |
dc.citation.startPage | 2054 | - |
dc.citation.endPage | 2068 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Endocrinology & Metabolism | - |
dc.relation.journalWebOfScienceCategory | Endocrinology & Metabolism | - |
dc.subject.keywordPlus | PYRUVATE-DEHYDROGENASE COMPLEX | - |
dc.subject.keywordPlus | TRANSCRIPTION FACTOR | - |
dc.subject.keywordPlus | INDUCED ACTIVATION | - |
dc.subject.keywordPlus | LEYDIG-CELLS | - |
dc.subject.keywordPlus | CYCLIC-AMP | - |
dc.subject.keywordPlus | GLUCONEOGENESIS | - |
dc.subject.keywordPlus | GLUCOSE | - |
dc.subject.keywordPlus | METABOLISM | - |
dc.subject.keywordPlus | CREB | - |
dc.subject.keywordPlus | PHOSPHORYLATION | - |
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
(02841) 서울특별시 성북구 안암로 14502-3290-1114
COPYRIGHT © 2021 Korea University. All Rights Reserved.
Certain data included herein are derived from the © Web of Science of Clarivate Analytics. All rights reserved.
You may not copy or re-distribute this material in whole or in part without the prior written consent of Clarivate Analytics.