Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine
The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a li...
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| creator | Cabrae, Régine Dubuquoy, Céline Caüzac, Michèle Morzyglod, Lucille Guilmeau, Sandra Noblet, Bénédicte Fève, Bruno Postic, Catherine Burnol, Anne-Françoise Moldes, Marthe |
| description | The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity,
in vivo
in mouse liver and
in vitro
in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway. |
| doi_str_mv | 10.1038/s41598-020-61869-4 |
| format | Article |
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in vivo
in mouse liver and
in vitro
in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-61869-4</identifier><identifier>PMID: 32198362</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/89 ; 13/95 ; 38 ; 631/443/319/1557 ; 631/80/86/2367 ; 64 ; 64/60 ; Acyltransferase ; Acyltransferases - metabolism ; Animals ; beta Catenin - drug effects ; beta Catenin - metabolism ; Cellular Biology ; Desaturase ; Fatty Acids, Monounsaturated - pharmacology ; Hepatocytes ; Hepatocytes - metabolism ; Homeostasis ; Humanities and Social Sciences ; Insulin ; Insulin - metabolism ; Life Sciences ; Lipogenesis ; Lipogenesis - drug effects ; Liver ; Liver - metabolism ; Liver - pathology ; Male ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred C57BL ; multidisciplinary ; Nutrition ; Palmitic acid ; Rapamycin ; Science ; Science (multidisciplinary) ; Signal transduction ; Stearoyl-CoA desaturase ; Stearoyl-CoA Desaturase - genetics ; Stearoyl-CoA Desaturase - metabolism ; Sterol Regulatory Element Binding Protein 1 - metabolism ; Transcription ; Wnt protein ; Wnt Signaling Pathway - drug effects ; Wnt Signaling Pathway - physiology ; Wortmannin ; β-Catenin</subject><ispartof>Scientific reports, 2020-03, Vol.10 (1), p.5186-5186, Article 5186</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-78c111978090c641f6c97f5040199074d3206ae6b3d59cc36bf6dcae6debc3ab3</citedby><cites>FETCH-LOGICAL-c508t-78c111978090c641f6c97f5040199074d3206ae6b3d59cc36bf6dcae6debc3ab3</cites><orcidid>0000-0002-8260-1218</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083857/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083857/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32198362$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04236207$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Cabrae, Régine</creatorcontrib><creatorcontrib>Dubuquoy, Céline</creatorcontrib><creatorcontrib>Caüzac, Michèle</creatorcontrib><creatorcontrib>Morzyglod, Lucille</creatorcontrib><creatorcontrib>Guilmeau, Sandra</creatorcontrib><creatorcontrib>Noblet, Bénédicte</creatorcontrib><creatorcontrib>Fève, Bruno</creatorcontrib><creatorcontrib>Postic, Catherine</creatorcontrib><creatorcontrib>Burnol, Anne-Françoise</creatorcontrib><creatorcontrib>Moldes, Marthe</creatorcontrib><title>Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity,
in vivo
in mouse liver and
in vitro
in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.</description><subject>13</subject><subject>13/89</subject><subject>13/95</subject><subject>38</subject><subject>631/443/319/1557</subject><subject>631/80/86/2367</subject><subject>64</subject><subject>64/60</subject><subject>Acyltransferase</subject><subject>Acyltransferases - metabolism</subject><subject>Animals</subject><subject>beta Catenin - drug effects</subject><subject>beta Catenin - metabolism</subject><subject>Cellular Biology</subject><subject>Desaturase</subject><subject>Fatty Acids, Monounsaturated - pharmacology</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Life Sciences</subject><subject>Lipogenesis</subject><subject>Lipogenesis - drug effects</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Male</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>multidisciplinary</subject><subject>Nutrition</subject><subject>Palmitic acid</subject><subject>Rapamycin</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>Stearoyl-CoA desaturase</subject><subject>Stearoyl-CoA Desaturase - genetics</subject><subject>Stearoyl-CoA Desaturase - metabolism</subject><subject>Sterol Regulatory Element Binding Protein 1 - metabolism</subject><subject>Transcription</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway - drug effects</subject><subject>Wnt Signaling Pathway - physiology</subject><subject>Wortmannin</subject><subject>β-Catenin</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc1u1DAQxyMEolXpC3BAlrjAIXT8Ece-IK1WlFZaqT0UcbQcx_mosvZiOyv1tXgQnqluU0rbA77YmvnNf8bzL4r3GL5goOIkMlxJUQKBkmPBZcleFYcEWFUSSsjrJ--D4jjGa8inIpJh-bY4oARLQTk5LJpzF-dpdEibNO51shENdqfTaNBPl07-_C5NDroMxLF3OpM9SkPwcz-gmKwO_mYq136FWht1moOOFmGkXYsufTDzbnT2XfGm01O0xw_3UfHj9NvV-qzcXHw_X682palApLIWBmMsawESDGe440bWXQUMsJRQs5YS4NryhraVNIbypuOtyYHWNobqhh4VXxfd3dxsbWusS0FPahfGrQ43yutRPc-4cVC936saBBVVnQU-LwLDi7Kz1UbdxYCRvDSo9ziznx6aBf9rtjGp7RiNnSbtrJ-jIlRgTirBIKMfX6DXfg55l_cUAM2YyBRZKBN8jMF2jxNgUHeOq8VxlR1X944rlos-PP3yY8lffzNAFyDmlOtt-Nf7P7K3D0e3Rg</recordid><startdate>20200320</startdate><enddate>20200320</enddate><creator>Cabrae, Régine</creator><creator>Dubuquoy, Céline</creator><creator>Caüzac, Michèle</creator><creator>Morzyglod, Lucille</creator><creator>Guilmeau, Sandra</creator><creator>Noblet, Bénédicte</creator><creator>Fève, Bruno</creator><creator>Postic, Catherine</creator><creator>Burnol, Anne-Françoise</creator><creator>Moldes, Marthe</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8260-1218</orcidid></search><sort><creationdate>20200320</creationdate><title>Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine</title><author>Cabrae, Régine ; Dubuquoy, Céline ; Caüzac, Michèle ; Morzyglod, Lucille ; Guilmeau, Sandra ; Noblet, Bénédicte ; Fève, Bruno ; Postic, Catherine ; Burnol, Anne-Françoise ; Moldes, Marthe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-78c111978090c641f6c97f5040199074d3206ae6b3d59cc36bf6dcae6debc3ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13</topic><topic>13/89</topic><topic>13/95</topic><topic>38</topic><topic>631/443/319/1557</topic><topic>631/80/86/2367</topic><topic>64</topic><topic>64/60</topic><topic>Acyltransferase</topic><topic>Acyltransferases - metabolism</topic><topic>Animals</topic><topic>beta Catenin - drug effects</topic><topic>beta Catenin - metabolism</topic><topic>Cellular Biology</topic><topic>Desaturase</topic><topic>Fatty Acids, Monounsaturated - pharmacology</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Life Sciences</topic><topic>Lipogenesis</topic><topic>Lipogenesis - drug effects</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Male</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>multidisciplinary</topic><topic>Nutrition</topic><topic>Palmitic acid</topic><topic>Rapamycin</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal transduction</topic><topic>Stearoyl-CoA desaturase</topic><topic>Stearoyl-CoA Desaturase - genetics</topic><topic>Stearoyl-CoA Desaturase - metabolism</topic><topic>Sterol Regulatory Element Binding Protein 1 - metabolism</topic><topic>Transcription</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway - drug effects</topic><topic>Wnt Signaling Pathway - physiology</topic><topic>Wortmannin</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cabrae, Régine</creatorcontrib><creatorcontrib>Dubuquoy, Céline</creatorcontrib><creatorcontrib>Caüzac, Michèle</creatorcontrib><creatorcontrib>Morzyglod, Lucille</creatorcontrib><creatorcontrib>Guilmeau, Sandra</creatorcontrib><creatorcontrib>Noblet, Bénédicte</creatorcontrib><creatorcontrib>Fève, Bruno</creatorcontrib><creatorcontrib>Postic, Catherine</creatorcontrib><creatorcontrib>Burnol, Anne-Françoise</creatorcontrib><creatorcontrib>Moldes, Marthe</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cabrae, Régine</au><au>Dubuquoy, Céline</au><au>Caüzac, Michèle</au><au>Morzyglod, Lucille</au><au>Guilmeau, Sandra</au><au>Noblet, Bénédicte</au><au>Fève, Bruno</au><au>Postic, Catherine</au><au>Burnol, Anne-Françoise</au><au>Moldes, Marthe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-03-20</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>5186</spage><epage>5186</epage><pages>5186-5186</pages><artnum>5186</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity,
in vivo
in mouse liver and
in vitro
in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32198362</pmid><doi>10.1038/s41598-020-61869-4</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8260-1218</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/89 13/95 38 631/443/319/1557 631/80/86/2367 64 64/60 Acyltransferase Acyltransferases - metabolism Animals beta Catenin - drug effects beta Catenin - metabolism Cellular Biology Desaturase Fatty Acids, Monounsaturated - pharmacology Hepatocytes Hepatocytes - metabolism Homeostasis Humanities and Social Sciences Insulin Insulin - metabolism Life Sciences Lipogenesis Lipogenesis - drug effects Liver Liver - metabolism Liver - pathology Male Membrane Proteins - metabolism Mice Mice, Inbred C57BL multidisciplinary Nutrition Palmitic acid Rapamycin Science Science (multidisciplinary) Signal transduction Stearoyl-CoA desaturase Stearoyl-CoA Desaturase - genetics Stearoyl-CoA Desaturase - metabolism Sterol Regulatory Element Binding Protein 1 - metabolism Transcription Wnt protein Wnt Signaling Pathway - drug effects Wnt Signaling Pathway - physiology Wortmannin β-Catenin |
| title | Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine |
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