AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver
Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we dem...
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| creator | Liu, Shudong Jing, Fei Yu, Chunxiao Gao, Ling Qin, Yejun Zhao, Jiajun |
| description | Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH). |
| doi_str_mv | 10.1371/journal.pone.0124951 |
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Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH).</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0124951</identifier><identifier>PMID: 25933205</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Adenosine ; Aminoimidazole Carboxamide - analogs & derivatives ; Aminoimidazole Carboxamide - pharmacology ; AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Atherosclerosis ; Biosynthesis ; Cardiovascular disease ; Cholesterol ; Clinical medicine ; Diabetes ; Endocrinology ; Enzyme Activation - drug effects ; Enzymes ; Fatty liver ; Fluorescent Antibody Technique ; Gene expression ; Hep G2 Cells ; Hospitals ; Humans ; Hydroxymethylglutaryl-CoA Synthase - metabolism ; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent - metabolism ; Hypercholesterolemia ; Hypothyroidism ; Immunoglobulins ; Kinases ; Lipids ; Liver ; Liver - drug effects ; Liver - enzymology ; Liver - metabolism ; Liver - pathology ; Low density lipoprotein ; Metabolism ; Mice, Knockout ; Models, Biological ; Phosphorylation ; Phosphorylation - drug effects ; Phosphothreonine - metabolism ; Protein binding ; Protein-serine/threonine kinase ; Proteins ; Receptors, Thyrotropin - metabolism ; Ribonucleotides - pharmacology ; Rodents ; Signal Transduction - drug effects ; Steatosis ; Sterol Regulatory Element Binding Protein 2 - metabolism ; Sterol regulatory element-binding protein ; Sterols ; Studies ; Threonine ; Thyroid ; Thyroid gland ; Thyroid hormones ; Thyroid-stimulating hormone ; Thyrotropin ; Thyrotropin - metabolism ; Thyrotropin - pharmacology ; Triglycerides ; Up-Regulation - drug effects</subject><ispartof>PloS one, 2015-05, Vol.10 (5), p.e0124951-e0124951</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Liu et al 2015 Liu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-453b5194dde02d02f2b6c154cc9ca73e6ea41a7c6a6d6cec00e02b6fe0ff38023</citedby><cites>FETCH-LOGICAL-c758t-453b5194dde02d02f2b6c154cc9ca73e6ea41a7c6a6d6cec00e02b6fe0ff38023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416759/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416759/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2930,23873,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25933205$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Zang, Mengwei</contributor><creatorcontrib>Liu, Shudong</creatorcontrib><creatorcontrib>Jing, Fei</creatorcontrib><creatorcontrib>Yu, Chunxiao</creatorcontrib><creatorcontrib>Gao, Ling</creatorcontrib><creatorcontrib>Qin, Yejun</creatorcontrib><creatorcontrib>Zhao, Jiajun</creatorcontrib><title>AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH).</description><subject>Activation</subject><subject>Adenosine</subject><subject>Aminoimidazole Carboxamide - analogs & derivatives</subject><subject>Aminoimidazole Carboxamide - pharmacology</subject><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Atherosclerosis</subject><subject>Biosynthesis</subject><subject>Cardiovascular disease</subject><subject>Cholesterol</subject><subject>Clinical medicine</subject><subject>Diabetes</subject><subject>Endocrinology</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzymes</subject><subject>Fatty liver</subject><subject>Fluorescent Antibody Technique</subject><subject>Gene expression</subject><subject>Hep G2 Cells</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Synthase - metabolism</subject><subject>Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent - metabolism</subject><subject>Hypercholesterolemia</subject><subject>Hypothyroidism</subject><subject>Immunoglobulins</subject><subject>Kinases</subject><subject>Lipids</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Low density lipoprotein</subject><subject>Metabolism</subject><subject>Mice, Knockout</subject><subject>Models, Biological</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Phosphothreonine - metabolism</subject><subject>Protein binding</subject><subject>Protein-serine/threonine kinase</subject><subject>Proteins</subject><subject>Receptors, Thyrotropin - metabolism</subject><subject>Ribonucleotides - pharmacology</subject><subject>Rodents</subject><subject>Signal Transduction - drug effects</subject><subject>Steatosis</subject><subject>Sterol Regulatory Element Binding Protein 2 - metabolism</subject><subject>Sterol regulatory element-binding protein</subject><subject>Sterols</subject><subject>Studies</subject><subject>Threonine</subject><subject>Thyroid</subject><subject>Thyroid gland</subject><subject>Thyroid hormones</subject><subject>Thyroid-stimulating hormone</subject><subject>Thyrotropin</subject><subject>Thyrotropin - metabolism</subject><subject>Thyrotropin - pharmacology</subject><subject>Triglycerides</subject><subject>Up-Regulation - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1v0zAUhiMEYlvhHyCIhITgIq2_k9xMCtVYKzqtage3lus4ras0LrHTsX-PQ7OpQbtAvrB1_Jz3-By_QfAOgiHEMRxtTVNXohzuTaWGACKSUvgiOIcpRhFDAL88OZ8FF9ZuAaA4Yex1cIZoijEC9DyYZdNxtoimVd5IlYeZdPognDZVaIowu5l_D6fVRq-0s-HdcjJaLq6-ziM0mtxcjxfhXLjNvXgIdRXO9EHVb4JXhSitetvtg-DHt6u78SSa3V77MrNIxjRxEaF4RWFK8lwBlANUoBWTkBIpUylirJgSBIpYMsFyJpUEwHMrVihQFDgBCA-CD0fdfWks7wZhOWRxzAht2xwE0yORG7Hl-1rvRP3AjdD8b8DUay5qp2WpuExhAqSUiWAJYTgXKSWAxTQlGKJUJl7rsqvWrHYql6pytSh7ov2bSm_42hw4IbDV8QKfO4Ha_GqUdXynrVRlKSplmuO7k8QXiz368R_0-e46ai18A7oqjK8rW1GeEYQTTGPSTmn4DOVXrnZaetcU2sd7CV96CZ5x6rdbi8ZaPl0u_p-9_dlnP52wGyVKt7GmbFqb2T5IjqCsjbW1Kp6GDAFvTf84Dd6annem92nvTz_oKenR5fgPDrP3wA</recordid><startdate>20150501</startdate><enddate>20150501</enddate><creator>Liu, Shudong</creator><creator>Jing, Fei</creator><creator>Yu, Chunxiao</creator><creator>Gao, Ling</creator><creator>Qin, Yejun</creator><creator>Zhao, Jiajun</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150501</creationdate><title>AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver</title><author>Liu, Shudong ; Jing, Fei ; Yu, Chunxiao ; Gao, Ling ; Qin, Yejun ; Zhao, Jiajun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-453b5194dde02d02f2b6c154cc9ca73e6ea41a7c6a6d6cec00e02b6fe0ff38023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Activation</topic><topic>Adenosine</topic><topic>Aminoimidazole Carboxamide - analogs & derivatives</topic><topic>Aminoimidazole Carboxamide - pharmacology</topic><topic>AMP</topic><topic>AMP-activated protein kinase</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Atherosclerosis</topic><topic>Biosynthesis</topic><topic>Cardiovascular disease</topic><topic>Cholesterol</topic><topic>Clinical medicine</topic><topic>Diabetes</topic><topic>Endocrinology</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzymes</topic><topic>Fatty liver</topic><topic>Fluorescent Antibody Technique</topic><topic>Gene expression</topic><topic>Hep G2 Cells</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Synthase - metabolism</topic><topic>Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent - metabolism</topic><topic>Hypercholesterolemia</topic><topic>Hypothyroidism</topic><topic>Immunoglobulins</topic><topic>Kinases</topic><topic>Lipids</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Low density lipoprotein</topic><topic>Metabolism</topic><topic>Mice, Knockout</topic><topic>Models, Biological</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Phosphothreonine - metabolism</topic><topic>Protein binding</topic><topic>Protein-serine/threonine kinase</topic><topic>Proteins</topic><topic>Receptors, Thyrotropin - metabolism</topic><topic>Ribonucleotides - pharmacology</topic><topic>Rodents</topic><topic>Signal Transduction - drug effects</topic><topic>Steatosis</topic><topic>Sterol Regulatory Element Binding Protein 2 - metabolism</topic><topic>Sterol regulatory element-binding protein</topic><topic>Sterols</topic><topic>Studies</topic><topic>Threonine</topic><topic>Thyroid</topic><topic>Thyroid gland</topic><topic>Thyroid hormones</topic><topic>Thyroid-stimulating hormone</topic><topic>Thyrotropin</topic><topic>Thyrotropin - metabolism</topic><topic>Thyrotropin - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Shudong</au><au>Jing, Fei</au><au>Yu, Chunxiao</au><au>Gao, Ling</au><au>Qin, Yejun</au><au>Zhao, Jiajun</au><au>Zang, Mengwei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-05-01</date><risdate>2015</risdate><volume>10</volume><issue>5</issue><spage>e0124951</spage><epage>e0124951</epage><pages>e0124951-e0124951</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP-activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH-stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH).</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25933205</pmid><doi>10.1371/journal.pone.0124951</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Activation Adenosine Aminoimidazole Carboxamide - analogs & derivatives Aminoimidazole Carboxamide - pharmacology AMP AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Atherosclerosis Biosynthesis Cardiovascular disease Cholesterol Clinical medicine Diabetes Endocrinology Enzyme Activation - drug effects Enzymes Fatty liver Fluorescent Antibody Technique Gene expression Hep G2 Cells Hospitals Humans Hydroxymethylglutaryl-CoA Synthase - metabolism Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent - metabolism Hypercholesterolemia Hypothyroidism Immunoglobulins Kinases Lipids Liver Liver - drug effects Liver - enzymology Liver - metabolism Liver - pathology Low density lipoprotein Metabolism Mice, Knockout Models, Biological Phosphorylation Phosphorylation - drug effects Phosphothreonine - metabolism Protein binding Protein-serine/threonine kinase Proteins Receptors, Thyrotropin - metabolism Ribonucleotides - pharmacology Rodents Signal Transduction - drug effects Steatosis Sterol Regulatory Element Binding Protein 2 - metabolism Sterol regulatory element-binding protein Sterols Studies Threonine Thyroid Thyroid gland Thyroid hormones Thyroid-stimulating hormone Thyrotropin Thyrotropin - metabolism Thyrotropin - pharmacology Triglycerides Up-Regulation - drug effects |
| title | AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-04T12%3A32%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=AICAR-Induced%20Activation%20of%20AMPK%20Inhibits%20TSH/SREBP-2/HMGCR%20Pathway%20in%20Liver&rft.jtitle=PloS%20one&rft.au=Liu,%20Shudong&rft.date=2015-05-01&rft.volume=10&rft.issue=5&rft.spage=e0124951&rft.epage=e0124951&rft.pages=e0124951-e0124951&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0124951&rft_dat=%3Cgale_plos_%3EA423835742%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1677645005&rft_id=info:pmid/25933205&rft_galeid=A423835742&rft_doaj_id=oai_doaj_org_article_c9180ccc8a68463da9540675943129c8&rfr_iscdi=true |