Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects
Objective: The aim of this study was to evaluate whether dysregulation of molecules involved in FOXO1-dependent insulin signaling in the liver is associated with de novo lipogenesis (DNL) and altered lipid metabolism in severely obese subjects. Design: Observational retrospective study. Subjects: We...
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| Veröffentlicht in: | International Journal of Obesity 2013-07, Vol.37 (7), p.986-992 |
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| creator | Rametta, R Mozzi, E Dongiovanni, P Motta, B M Milano, M Roviaro, G Fargion, S Valenti, L |
| description | Objective:
The aim of this study was to evaluate whether dysregulation of molecules involved in FOXO1-dependent insulin signaling in the liver is associated with
de novo
lipogenesis (DNL) and altered lipid metabolism in severely obese subjects.
Design:
Observational retrospective study.
Subjects:
We considered 71 obese subjects (age 20–68 years; body mass index (BMI)>40 kg m
−2
or BMI>35 kg m
−2
in the presence of metabolic complications) classified into three groups according to liver histology: normal liver (
n
=12), simple steatosis (
n
=27) and nonalcoholic steatohepatitis (NASH;
n
=32). Key nodes in insulin signaling and gene expression of molecules implicated in insulin-dependent glucoregulatory pathway and DNL were evaluated by quantitative real-time PCR and western blotting.
Results:
Patients with steatosis had decreased phosphorylation of the insulin kinase AKT1, mediating insulin receptor signaling, and the transcription factor FOXO1, which was therefore more active mediating insulin resistance at transcriptional level. Despite no changes in insulin receptor substrate (IRS)1 mRNA levels, the mRNA and protein levels of the FOXO1 target IRS2 increased progressively with the severity of steatosis from normal liver to NASH. IRS2 expression was correlated with the severity of steatosis, dyslipidemia and liver damage. In patients with NASH, upregulation of IRS2 was associated with preserved activation of AKT2, mediating the stimulating effect of insulin on DNL, and overexpression of its target sterol regulatory element-binding protein 1c (SREBP1c), inducing DNL at transcriptional level. Both FOXO1 and SREBP1c overexpression converged on upregulation of glucokinase, providing substrates for DNL, in NASH patients.
Conclusion:
Differential regulation of IRS1 and IRS2 and of their downstream effectors AKT1 and AKT2 is consistent with upregulation of FOXO1 and may justify the paradoxical state of insulin resistance relative to the glucoregulatory pathway and augmented insulin sensitivity of the liporegulatory pathway typical of steatosis and the metabolic syndrome in obese patients. |
| doi_str_mv | 10.1038/ijo.2012.181 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_1837322480</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A338523900</galeid><sourcerecordid>A338523900</sourcerecordid><originalsourceid>FETCH-LOGICAL-c551t-5a3ccfc8cb341388d78d3b34277a476b8eb5d9b17f34fe4460a3c5a50a9788d83</originalsourceid><addsrcrecordid>eNqF0kGL1TAQAOAgivtcvXmWgCh7sM-kaZr0uCy6Lix40XNJ0-m-PNqkZlLUs3_clPd0d2VBemjJfDNhpkPIS862nAn93u3DtmS83HLNH5ENr1RdyKpRj8mGCaYKJmt5Qp4h7hljUrLyKTkpRWacyw35deVtBIPQU-dxGZ2nESzMKUSKS4cpmgS0pPBjjoDogqcOqUEM1uVIT7-7tKOYwKSwg9kkl9a476kZE8QMRje7nk6QTBdGh1O-h4YOENb6e7AJn5MngxkRXhzfp-Trxw9fLj4V158vry7OrwsrJU-FNMLawWrbiYoLrXule5G_S6VMbrrT0Mm-6bgaRDVAVdUsJ0gjmWlU1lqckrND3TmGbwtgaieHFsbReAgLtlwLJcqy0uz_VDRNWcumXunrf-g-LNHnRlala6mZ1LfqxozQOj-EPFm7Fm3PhdCyFA1ba20fUPnpYXI2eBhcPr-X8PZOwg7y0HcYxiXlH4X34bsDtDEgRhjaObrJxJ8tZ-26R23eo3bdozwGnvmrY1NLN0H_F_9ZnAzeHIFBa8YhGm8d3jpVac6qte_i4DCH_A3EO9N56OLfsdHeDg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1398658058</pqid></control><display><type>article</type><title>Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Nature Journals Online</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Rametta, R ; Mozzi, E ; Dongiovanni, P ; Motta, B M ; Milano, M ; Roviaro, G ; Fargion, S ; Valenti, L</creator><creatorcontrib>Rametta, R ; Mozzi, E ; Dongiovanni, P ; Motta, B M ; Milano, M ; Roviaro, G ; Fargion, S ; Valenti, L</creatorcontrib><description>Objective:
The aim of this study was to evaluate whether dysregulation of molecules involved in FOXO1-dependent insulin signaling in the liver is associated with
de novo
lipogenesis (DNL) and altered lipid metabolism in severely obese subjects.
Design:
Observational retrospective study.
Subjects:
We considered 71 obese subjects (age 20–68 years; body mass index (BMI)>40 kg m
−2
or BMI>35 kg m
−2
in the presence of metabolic complications) classified into three groups according to liver histology: normal liver (
n
=12), simple steatosis (
n
=27) and nonalcoholic steatohepatitis (NASH;
n
=32). Key nodes in insulin signaling and gene expression of molecules implicated in insulin-dependent glucoregulatory pathway and DNL were evaluated by quantitative real-time PCR and western blotting.
Results:
Patients with steatosis had decreased phosphorylation of the insulin kinase AKT1, mediating insulin receptor signaling, and the transcription factor FOXO1, which was therefore more active mediating insulin resistance at transcriptional level. Despite no changes in insulin receptor substrate (IRS)1 mRNA levels, the mRNA and protein levels of the FOXO1 target IRS2 increased progressively with the severity of steatosis from normal liver to NASH. IRS2 expression was correlated with the severity of steatosis, dyslipidemia and liver damage. In patients with NASH, upregulation of IRS2 was associated with preserved activation of AKT2, mediating the stimulating effect of insulin on DNL, and overexpression of its target sterol regulatory element-binding protein 1c (SREBP1c), inducing DNL at transcriptional level. Both FOXO1 and SREBP1c overexpression converged on upregulation of glucokinase, providing substrates for DNL, in NASH patients.
Conclusion:
Differential regulation of IRS1 and IRS2 and of their downstream effectors AKT1 and AKT2 is consistent with upregulation of FOXO1 and may justify the paradoxical state of insulin resistance relative to the glucoregulatory pathway and augmented insulin sensitivity of the liporegulatory pathway typical of steatosis and the metabolic syndrome in obese patients.</description><identifier>ISSN: 0307-0565</identifier><identifier>EISSN: 1476-5497</identifier><identifier>DOI: 10.1038/ijo.2012.181</identifier><identifier>PMID: 23147115</identifier><identifier>CODEN: IJOBDP</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/443/319/2723 ; 631/80/86/2367 ; 692/699/1503/1607/2750 ; 692/699/2743/393 ; Adult ; Aged ; Biological and medical sciences ; Blotting, Western ; Body mass index ; Cellular signal transduction ; Cholesterol ; Diabetes ; Epidemiology ; Fatty Liver - genetics ; Fatty Liver - metabolism ; Fatty Liver - physiopathology ; Female ; Forkhead Box Protein O1 ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Gastroenterology. Liver. Pancreas. Abdomen ; Gastrointestinal surgery ; Gene Expression ; Glucose ; Health Promotion and Disease Prevention ; High density lipoprotein ; Histology ; Humans ; Insulin ; Insulin Receptor Substrate Proteins - genetics ; Insulin Receptor Substrate Proteins - metabolism ; Insulin resistance ; Insulin Resistance - genetics ; Internal Medicine ; Italy ; Kinases ; Lipid Metabolism ; Lipids ; Lipogenesis ; Liver ; Liver - metabolism ; Liver diseases ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolic disorders ; Metabolic syndrome ; Middle Aged ; Obesity ; Obesity, Morbid - genetics ; Obesity, Morbid - metabolism ; Obesity, Morbid - physiopathology ; original-article ; Other diseases. Semiology ; Oxidative Stress ; Pathophysiology ; Phosphorylation ; Physiological aspects ; Proteins ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Public Health ; Real-Time Polymerase Chain Reaction ; Receptors ; Retrospective Studies ; RNA, Messenger ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1 - genetics ; Sterol Regulatory Element Binding Protein 1 - metabolism ; Sterols ; Substrates</subject><ispartof>International Journal of Obesity, 2013-07, Vol.37 (7), p.986-992</ispartof><rights>Macmillan Publishers Limited 2013</rights><rights>2014 INIST-CNRS</rights><rights>COPYRIGHT 2013 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c551t-5a3ccfc8cb341388d78d3b34277a476b8eb5d9b17f34fe4460a3c5a50a9788d83</citedby><cites>FETCH-LOGICAL-c551t-5a3ccfc8cb341388d78d3b34277a476b8eb5d9b17f34fe4460a3c5a50a9788d83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ijo.2012.181$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ijo.2012.181$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27481048$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23147115$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rametta, R</creatorcontrib><creatorcontrib>Mozzi, E</creatorcontrib><creatorcontrib>Dongiovanni, P</creatorcontrib><creatorcontrib>Motta, B M</creatorcontrib><creatorcontrib>Milano, M</creatorcontrib><creatorcontrib>Roviaro, G</creatorcontrib><creatorcontrib>Fargion, S</creatorcontrib><creatorcontrib>Valenti, L</creatorcontrib><title>Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects</title><title>International Journal of Obesity</title><addtitle>Int J Obes</addtitle><addtitle>Int J Obes (Lond)</addtitle><description>Objective:
The aim of this study was to evaluate whether dysregulation of molecules involved in FOXO1-dependent insulin signaling in the liver is associated with
de novo
lipogenesis (DNL) and altered lipid metabolism in severely obese subjects.
Design:
Observational retrospective study.
Subjects:
We considered 71 obese subjects (age 20–68 years; body mass index (BMI)>40 kg m
−2
or BMI>35 kg m
−2
in the presence of metabolic complications) classified into three groups according to liver histology: normal liver (
n
=12), simple steatosis (
n
=27) and nonalcoholic steatohepatitis (NASH;
n
=32). Key nodes in insulin signaling and gene expression of molecules implicated in insulin-dependent glucoregulatory pathway and DNL were evaluated by quantitative real-time PCR and western blotting.
Results:
Patients with steatosis had decreased phosphorylation of the insulin kinase AKT1, mediating insulin receptor signaling, and the transcription factor FOXO1, which was therefore more active mediating insulin resistance at transcriptional level. Despite no changes in insulin receptor substrate (IRS)1 mRNA levels, the mRNA and protein levels of the FOXO1 target IRS2 increased progressively with the severity of steatosis from normal liver to NASH. IRS2 expression was correlated with the severity of steatosis, dyslipidemia and liver damage. In patients with NASH, upregulation of IRS2 was associated with preserved activation of AKT2, mediating the stimulating effect of insulin on DNL, and overexpression of its target sterol regulatory element-binding protein 1c (SREBP1c), inducing DNL at transcriptional level. Both FOXO1 and SREBP1c overexpression converged on upregulation of glucokinase, providing substrates for DNL, in NASH patients.
Conclusion:
Differential regulation of IRS1 and IRS2 and of their downstream effectors AKT1 and AKT2 is consistent with upregulation of FOXO1 and may justify the paradoxical state of insulin resistance relative to the glucoregulatory pathway and augmented insulin sensitivity of the liporegulatory pathway typical of steatosis and the metabolic syndrome in obese patients.</description><subject>631/443/319/2723</subject><subject>631/80/86/2367</subject><subject>692/699/1503/1607/2750</subject><subject>692/699/2743/393</subject><subject>Adult</subject><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Body mass index</subject><subject>Cellular signal transduction</subject><subject>Cholesterol</subject><subject>Diabetes</subject><subject>Epidemiology</subject><subject>Fatty Liver - genetics</subject><subject>Fatty Liver - metabolism</subject><subject>Fatty Liver - physiopathology</subject><subject>Female</subject><subject>Forkhead Box Protein O1</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gastrointestinal surgery</subject><subject>Gene Expression</subject><subject>Glucose</subject><subject>Health Promotion and Disease Prevention</subject><subject>High density lipoprotein</subject><subject>Histology</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin Receptor Substrate Proteins - genetics</subject><subject>Insulin Receptor Substrate Proteins - metabolism</subject><subject>Insulin resistance</subject><subject>Insulin Resistance - genetics</subject><subject>Internal Medicine</subject><subject>Italy</subject><subject>Kinases</subject><subject>Lipid Metabolism</subject><subject>Lipids</subject><subject>Lipogenesis</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver diseases</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Middle Aged</subject><subject>Obesity</subject><subject>Obesity, Morbid - genetics</subject><subject>Obesity, Morbid - metabolism</subject><subject>Obesity, Morbid - physiopathology</subject><subject>original-article</subject><subject>Other diseases. Semiology</subject><subject>Oxidative Stress</subject><subject>Pathophysiology</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Public Health</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Receptors</subject><subject>Retrospective Studies</subject><subject>RNA, Messenger</subject><subject>Signal Transduction</subject><subject>Sterol Regulatory Element Binding Protein 1 - genetics</subject><subject>Sterol Regulatory Element Binding Protein 1 - metabolism</subject><subject>Sterols</subject><subject>Substrates</subject><issn>0307-0565</issn><issn>1476-5497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</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><recordid>eNqF0kGL1TAQAOAgivtcvXmWgCh7sM-kaZr0uCy6Lix40XNJ0-m-PNqkZlLUs3_clPd0d2VBemjJfDNhpkPIS862nAn93u3DtmS83HLNH5ENr1RdyKpRj8mGCaYKJmt5Qp4h7hljUrLyKTkpRWacyw35deVtBIPQU-dxGZ2nESzMKUSKS4cpmgS0pPBjjoDogqcOqUEM1uVIT7-7tKOYwKSwg9kkl9a476kZE8QMRje7nk6QTBdGh1O-h4YOENb6e7AJn5MngxkRXhzfp-Trxw9fLj4V158vry7OrwsrJU-FNMLawWrbiYoLrXule5G_S6VMbrrT0Mm-6bgaRDVAVdUsJ0gjmWlU1lqckrND3TmGbwtgaieHFsbReAgLtlwLJcqy0uz_VDRNWcumXunrf-g-LNHnRlala6mZ1LfqxozQOj-EPFm7Fm3PhdCyFA1ba20fUPnpYXI2eBhcPr-X8PZOwg7y0HcYxiXlH4X34bsDtDEgRhjaObrJxJ8tZ-26R23eo3bdozwGnvmrY1NLN0H_F_9ZnAzeHIFBa8YhGm8d3jpVac6qte_i4DCH_A3EO9N56OLfsdHeDg</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Rametta, R</creator><creator>Mozzi, E</creator><creator>Dongiovanni, P</creator><creator>Motta, B M</creator><creator>Milano, M</creator><creator>Roviaro, G</creator><creator>Fargion, S</creator><creator>Valenti, L</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</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>7T2</scope><scope>7TK</scope><scope>7TS</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</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>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20130701</creationdate><title>Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects</title><author>Rametta, R ; Mozzi, E ; Dongiovanni, P ; Motta, B M ; Milano, M ; Roviaro, G ; Fargion, S ; Valenti, L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c551t-5a3ccfc8cb341388d78d3b34277a476b8eb5d9b17f34fe4460a3c5a50a9788d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/443/319/2723</topic><topic>631/80/86/2367</topic><topic>692/699/1503/1607/2750</topic><topic>692/699/2743/393</topic><topic>Adult</topic><topic>Aged</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Body mass index</topic><topic>Cellular signal transduction</topic><topic>Cholesterol</topic><topic>Diabetes</topic><topic>Epidemiology</topic><topic>Fatty Liver - genetics</topic><topic>Fatty Liver - metabolism</topic><topic>Fatty Liver - physiopathology</topic><topic>Female</topic><topic>Forkhead Box Protein O1</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gastrointestinal surgery</topic><topic>Gene Expression</topic><topic>Glucose</topic><topic>Health Promotion and Disease Prevention</topic><topic>High density lipoprotein</topic><topic>Histology</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin Receptor Substrate Proteins - genetics</topic><topic>Insulin Receptor Substrate Proteins - metabolism</topic><topic>Insulin resistance</topic><topic>Insulin Resistance - genetics</topic><topic>Internal Medicine</topic><topic>Italy</topic><topic>Kinases</topic><topic>Lipid Metabolism</topic><topic>Lipids</topic><topic>Lipogenesis</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver diseases</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Metabolic disorders</topic><topic>Metabolic syndrome</topic><topic>Middle Aged</topic><topic>Obesity</topic><topic>Obesity, Morbid - genetics</topic><topic>Obesity, Morbid - metabolism</topic><topic>Obesity, Morbid - physiopathology</topic><topic>original-article</topic><topic>Other diseases. Semiology</topic><topic>Oxidative Stress</topic><topic>Pathophysiology</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Public Health</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Receptors</topic><topic>Retrospective Studies</topic><topic>RNA, Messenger</topic><topic>Signal Transduction</topic><topic>Sterol Regulatory Element Binding Protein 1 - genetics</topic><topic>Sterol Regulatory Element Binding Protein 1 - metabolism</topic><topic>Sterols</topic><topic>Substrates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rametta, R</creatorcontrib><creatorcontrib>Mozzi, E</creatorcontrib><creatorcontrib>Dongiovanni, P</creatorcontrib><creatorcontrib>Motta, B M</creatorcontrib><creatorcontrib>Milano, M</creatorcontrib><creatorcontrib>Roviaro, G</creatorcontrib><creatorcontrib>Fargion, S</creatorcontrib><creatorcontrib>Valenti, L</creatorcontrib><collection>Pascal-Francis</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 and Safety Science Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Agricultural Science Collection</collection><collection>ProQuest - Health & Medical Complete保健、医学与药学数据库</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (Proquest)</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)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</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>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Psychology Journals</collection><collection>ProQuest Biological Science Journals</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 China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>International Journal of Obesity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rametta, R</au><au>Mozzi, E</au><au>Dongiovanni, P</au><au>Motta, B M</au><au>Milano, M</au><au>Roviaro, G</au><au>Fargion, S</au><au>Valenti, L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects</atitle><jtitle>International Journal of Obesity</jtitle><stitle>Int J Obes</stitle><addtitle>Int J Obes (Lond)</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>37</volume><issue>7</issue><spage>986</spage><epage>992</epage><pages>986-992</pages><issn>0307-0565</issn><eissn>1476-5497</eissn><coden>IJOBDP</coden><abstract>Objective:
The aim of this study was to evaluate whether dysregulation of molecules involved in FOXO1-dependent insulin signaling in the liver is associated with
de novo
lipogenesis (DNL) and altered lipid metabolism in severely obese subjects.
Design:
Observational retrospective study.
Subjects:
We considered 71 obese subjects (age 20–68 years; body mass index (BMI)>40 kg m
−2
or BMI>35 kg m
−2
in the presence of metabolic complications) classified into three groups according to liver histology: normal liver (
n
=12), simple steatosis (
n
=27) and nonalcoholic steatohepatitis (NASH;
n
=32). Key nodes in insulin signaling and gene expression of molecules implicated in insulin-dependent glucoregulatory pathway and DNL were evaluated by quantitative real-time PCR and western blotting.
Results:
Patients with steatosis had decreased phosphorylation of the insulin kinase AKT1, mediating insulin receptor signaling, and the transcription factor FOXO1, which was therefore more active mediating insulin resistance at transcriptional level. Despite no changes in insulin receptor substrate (IRS)1 mRNA levels, the mRNA and protein levels of the FOXO1 target IRS2 increased progressively with the severity of steatosis from normal liver to NASH. IRS2 expression was correlated with the severity of steatosis, dyslipidemia and liver damage. In patients with NASH, upregulation of IRS2 was associated with preserved activation of AKT2, mediating the stimulating effect of insulin on DNL, and overexpression of its target sterol regulatory element-binding protein 1c (SREBP1c), inducing DNL at transcriptional level. Both FOXO1 and SREBP1c overexpression converged on upregulation of glucokinase, providing substrates for DNL, in NASH patients.
Conclusion:
Differential regulation of IRS1 and IRS2 and of their downstream effectors AKT1 and AKT2 is consistent with upregulation of FOXO1 and may justify the paradoxical state of insulin resistance relative to the glucoregulatory pathway and augmented insulin sensitivity of the liporegulatory pathway typical of steatosis and the metabolic syndrome in obese patients.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23147115</pmid><doi>10.1038/ijo.2012.181</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0307-0565 |
| ispartof | International Journal of Obesity, 2013-07, Vol.37 (7), p.986-992 |
| issn | 0307-0565 1476-5497 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1837322480 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online; EZB-FREE-00999 freely available EZB journals |
| subjects | 631/443/319/2723 631/80/86/2367 692/699/1503/1607/2750 692/699/2743/393 Adult Aged Biological and medical sciences Blotting, Western Body mass index Cellular signal transduction Cholesterol Diabetes Epidemiology Fatty Liver - genetics Fatty Liver - metabolism Fatty Liver - physiopathology Female Forkhead Box Protein O1 Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gastroenterology. Liver. Pancreas. Abdomen Gastrointestinal surgery Gene Expression Glucose Health Promotion and Disease Prevention High density lipoprotein Histology Humans Insulin Insulin Receptor Substrate Proteins - genetics Insulin Receptor Substrate Proteins - metabolism Insulin resistance Insulin Resistance - genetics Internal Medicine Italy Kinases Lipid Metabolism Lipids Lipogenesis Liver Liver - metabolism Liver diseases Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Medicine Medicine & Public Health Metabolic Diseases Metabolic disorders Metabolic syndrome Middle Aged Obesity Obesity, Morbid - genetics Obesity, Morbid - metabolism Obesity, Morbid - physiopathology original-article Other diseases. Semiology Oxidative Stress Pathophysiology Phosphorylation Physiological aspects Proteins Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Public Health Real-Time Polymerase Chain Reaction Receptors Retrospective Studies RNA, Messenger Signal Transduction Sterol Regulatory Element Binding Protein 1 - genetics Sterol Regulatory Element Binding Protein 1 - metabolism Sterols Substrates |
| title | Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T07%3A38%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Increased%20insulin%20receptor%20substrate%202%20expression%20is%20associated%20with%20steatohepatitis%20and%20altered%20lipid%20metabolism%20in%20obese%20subjects&rft.jtitle=International%20Journal%20of%20Obesity&rft.au=Rametta,%20R&rft.date=2013-07-01&rft.volume=37&rft.issue=7&rft.spage=986&rft.epage=992&rft.pages=986-992&rft.issn=0307-0565&rft.eissn=1476-5497&rft.coden=IJOBDP&rft_id=info:doi/10.1038/ijo.2012.181&rft_dat=%3Cgale_proqu%3EA338523900%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1398658058&rft_id=info:pmid/23147115&rft_galeid=A338523900&rfr_iscdi=true |