Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression

The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced t...

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Published in:Endocrinology (Philadelphia) 2014-08, Vol.155 (8), p.2924-2931
Main Authors: Min, Ae-Kyung, Bae, Kwi-Hyun, Jung, Yun-A, Choi, Yeon-Kyung, Kim, Mi-Jin, Kim, Ji-Hyun, Jeon, Jae-Han, Kim, Jung-Guk, Lee, In-Kyu, Park, Keun-Gyu
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Language:English
Subjects:
Adenoviridae
Animals
Cell Line
Cyclic AMP - metabolism
Fasting - metabolism
Fibroblast Growth Factors - genetics
Fibroblast Growth Factors - metabolism
Food Deprivation
Gene Expression Regulation
Glucagon
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics
Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism
Promoter Regions, Genetic
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cited_by cdi_FETCH-LOGICAL-c439t-d9005dd58b4647506291c2948563f85b889f4ac3f4d64ff693d37eb2dae5482a3
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container_issue 8
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container_title Endocrinology (Philadelphia)
container_volume 155
creator Min, Ae-Kyung
Bae, Kwi-Hyun
Jung, Yun-A
Choi, Yeon-Kyung
Kim, Mi-Jin
Kim, Ji-Hyun
Jeon, Jae-Han
Kim, Jung-Guk
Lee, In-Kyu
Park, Keun-Gyu
description The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced transcription factors that induce FGF21 expression have not yet been fully studied. In the present study, we investigated whether the fasting-induced activation of the orphan nuclear receptor Nur77 increases hepatic FGF21 expression. We found that fasting induced hepatic Nur77 and FGF21 expression. Glucagon and forskolin increased Nur77 and FGF21 expression in vivo and in vitro, respectively, and adenovirus-mediated overexpression of Nur77 (Ad-Nur77) increased FGF21 expression in vitro and in vivo. Moreover, knockdown of endogenous Nur77 expression by siRNA-Nur77 abolished the effect of forskolin on FGF21 expression. The results of ChIP assays, EMSA, and mutagenesis analysis showed that Nur77 bound to the putative NBRE of the FGF21 promoter in cultured hepatocytes and fasting induced Nur77 binding to the FGF21 promoter in vivo. Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.
doi_str_mv 10.1210/en.2013-1758
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Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced transcription factors that induce FGF21 expression have not yet been fully studied. In the present study, we investigated whether the fasting-induced activation of the orphan nuclear receptor Nur77 increases hepatic FGF21 expression. We found that fasting induced hepatic Nur77 and FGF21 expression. Glucagon and forskolin increased Nur77 and FGF21 expression in vivo and in vitro, respectively, and adenovirus-mediated overexpression of Nur77 (Ad-Nur77) increased FGF21 expression in vitro and in vivo. Moreover, knockdown of endogenous Nur77 expression by siRNA-Nur77 abolished the effect of forskolin on FGF21 expression. The results of ChIP assays, EMSA, and mutagenesis analysis showed that Nur77 bound to the putative NBRE of the FGF21 promoter in cultured hepatocytes and fasting induced Nur77 binding to the FGF21 promoter in vivo. Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2013-1758</identifier><identifier>PMID: 24885573</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Adenoviridae ; Animals ; Cell Line ; Cyclic AMP - metabolism ; Fasting - metabolism ; Fibroblast Growth Factors - genetics ; Fibroblast Growth Factors - metabolism ; Food Deprivation ; Gene Expression Regulation ; Glucagon ; Liver - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics ; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism ; Promoter Regions, Genetic</subject><ispartof>Endocrinology (Philadelphia), 2014-08, Vol.155 (8), p.2924-2931</ispartof><rights>Copyright © 2014 by the Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-d9005dd58b4647506291c2948563f85b889f4ac3f4d64ff693d37eb2dae5482a3</citedby><cites>FETCH-LOGICAL-c439t-d9005dd58b4647506291c2948563f85b889f4ac3f4d64ff693d37eb2dae5482a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24885573$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Min, Ae-Kyung</creatorcontrib><creatorcontrib>Bae, Kwi-Hyun</creatorcontrib><creatorcontrib>Jung, Yun-A</creatorcontrib><creatorcontrib>Choi, Yeon-Kyung</creatorcontrib><creatorcontrib>Kim, Mi-Jin</creatorcontrib><creatorcontrib>Kim, Ji-Hyun</creatorcontrib><creatorcontrib>Jeon, Jae-Han</creatorcontrib><creatorcontrib>Kim, Jung-Guk</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Park, Keun-Gyu</creatorcontrib><title>Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. 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Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.</description><subject>Adenoviridae</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Cyclic AMP - metabolism</subject><subject>Fasting - metabolism</subject><subject>Fibroblast Growth Factors - genetics</subject><subject>Fibroblast Growth Factors - metabolism</subject><subject>Food Deprivation</subject><subject>Gene Expression Regulation</subject><subject>Glucagon</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics</subject><subject>Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism</subject><subject>Promoter Regions, Genetic</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNptkEtPwzAQhC0EoqVw44z8A0jxM3aOqOpLAiohOEeOvaGpWieyEwH_noQCJ06rnf12pBmErimZUkbJHfgpI5QnVEl9gsY0EzJRVJFTNCaDrhhTI3QR465fhRD8HI2Y0FpKxccINqHZGo-fOrsHE_AzWGjaOvRCUAo_gqtMCxEvTGwr_5asvessOLyCxrSVxYuqCHWx7694Ger3dtuTdvhnFM8_mgAxVrW_RGel2Ue4-pkT9LqYv8xWycNmuZ7dPyRW8KxNXEaIdE7qQqRCSZKyjFqWCS1TXmpZaJ2VwlheCpeKskwz7riCgjkDUmhm-ATdHn1tqGMMUOZNqA4mfOaU5ENbOfh8aCsf2urxmyPedMUB3B_8W08P8CMA3tU2VB6-E-W7ugu-D_K_7RfTL3YC</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Min, Ae-Kyung</creator><creator>Bae, Kwi-Hyun</creator><creator>Jung, Yun-A</creator><creator>Choi, Yeon-Kyung</creator><creator>Kim, Mi-Jin</creator><creator>Kim, Ji-Hyun</creator><creator>Jeon, Jae-Han</creator><creator>Kim, Jung-Guk</creator><creator>Lee, In-Kyu</creator><creator>Park, Keun-Gyu</creator><general>Endocrine Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20140801</creationdate><title>Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression</title><author>Min, Ae-Kyung ; Bae, Kwi-Hyun ; Jung, Yun-A ; Choi, Yeon-Kyung ; Kim, Mi-Jin ; Kim, Ji-Hyun ; Jeon, Jae-Han ; Kim, Jung-Guk ; Lee, In-Kyu ; Park, Keun-Gyu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-d9005dd58b4647506291c2948563f85b889f4ac3f4d64ff693d37eb2dae5482a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adenoviridae</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Cyclic AMP - metabolism</topic><topic>Fasting - metabolism</topic><topic>Fibroblast Growth Factors - genetics</topic><topic>Fibroblast Growth Factors - metabolism</topic><topic>Food Deprivation</topic><topic>Gene Expression Regulation</topic><topic>Glucagon</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics</topic><topic>Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism</topic><topic>Promoter Regions, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Min, Ae-Kyung</creatorcontrib><creatorcontrib>Bae, Kwi-Hyun</creatorcontrib><creatorcontrib>Jung, Yun-A</creatorcontrib><creatorcontrib>Choi, Yeon-Kyung</creatorcontrib><creatorcontrib>Kim, Mi-Jin</creatorcontrib><creatorcontrib>Kim, Ji-Hyun</creatorcontrib><creatorcontrib>Jeon, Jae-Han</creatorcontrib><creatorcontrib>Kim, Jung-Guk</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Park, Keun-Gyu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Min, Ae-Kyung</au><au>Bae, Kwi-Hyun</au><au>Jung, Yun-A</au><au>Choi, Yeon-Kyung</au><au>Kim, Mi-Jin</au><au>Kim, Ji-Hyun</au><au>Jeon, Jae-Han</au><au>Kim, Jung-Guk</au><au>Lee, In-Kyu</au><au>Park, Keun-Gyu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2014-08-01</date><risdate>2014</risdate><volume>155</volume><issue>8</issue><spage>2924</spage><epage>2931</epage><pages>2924-2931</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><notes>This work was supported by grants from the National Research Foundation of Korea funded by the Korean government (Ministry of Science, ICT and Future Planning) (2012R1A2A2A01043867 and 2012R1A2A1A03670452), and a grant from the Korea Health Technology R and D Project, Ministry of Health and Welfare, Republic of Korea (A111345).</notes><abstract>The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced transcription factors that induce FGF21 expression have not yet been fully studied. In the present study, we investigated whether the fasting-induced activation of the orphan nuclear receptor Nur77 increases hepatic FGF21 expression. We found that fasting induced hepatic Nur77 and FGF21 expression. Glucagon and forskolin increased Nur77 and FGF21 expression in vivo and in vitro, respectively, and adenovirus-mediated overexpression of Nur77 (Ad-Nur77) increased FGF21 expression in vitro and in vivo. Moreover, knockdown of endogenous Nur77 expression by siRNA-Nur77 abolished the effect of forskolin on FGF21 expression. The results of ChIP assays, EMSA, and mutagenesis analysis showed that Nur77 bound to the putative NBRE of the FGF21 promoter in cultured hepatocytes and fasting induced Nur77 binding to the FGF21 promoter in vivo. Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>24885573</pmid><doi>10.1210/en.2013-1758</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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source Oxford University Press Journals
subjects Adenoviridae
Animals
Cell Line
Cyclic AMP - metabolism
Fasting - metabolism
Fibroblast Growth Factors - genetics
Fibroblast Growth Factors - metabolism
Food Deprivation
Gene Expression Regulation
Glucagon
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics
Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism
Promoter Regions, Genetic
title Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression
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