4EBP2-regulated protein translation has a critical role in high-fat diet–induced insulin resistance in hepatocytes
A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under in...
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| Veröffentlicht in: | The Journal of biological chemistry 2023-11, Vol.299 (11), p.105315-105315, Article 105315 |
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| creator | Han, Xiao Yang, Fei Zhang, Zhengyi Hou, Zhanwu Sun, Qiong Su, Tian Lv, Weiqiang Wang, Zhen Yuan, Chao Zhang, Guanfei Pi, Xin Long, Jiangang Liu, Huadong |
| description | A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes. |
| doi_str_mv | 10.1016/j.jbc.2023.105315 |
| format | Article |
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Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1016/j.jbc.2023.105315</identifier><identifier>PMID: 37797700</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>4EBP2 ; Animals ; Carrier Proteins - metabolism ; Cell Line ; Diet, High-Fat - adverse effects ; hepatocyte ; Hepatocytes - metabolism ; Insulin - metabolism ; insulin resistance ; Insulin Resistance - physiology ; Male ; Mice ; Mice, Inbred C57BL ; palmitic acid ; Palmitic Acid - metabolism ; Protein Biosynthesis ; Proteomics</subject><ispartof>The Journal of biological chemistry, 2023-11, Vol.299 (11), p.105315-105315, Article 105315</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2023 The Authors 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c404t-69a665de1cf0de2f0a2d39ebba6ae77df59ee0871fa6856ba09a26988ec4f94c3</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/PMC10641227/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641227/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37797700$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Xiao</creatorcontrib><creatorcontrib>Yang, Fei</creatorcontrib><creatorcontrib>Zhang, Zhengyi</creatorcontrib><creatorcontrib>Hou, Zhanwu</creatorcontrib><creatorcontrib>Sun, Qiong</creatorcontrib><creatorcontrib>Su, Tian</creatorcontrib><creatorcontrib>Lv, Weiqiang</creatorcontrib><creatorcontrib>Wang, Zhen</creatorcontrib><creatorcontrib>Yuan, Chao</creatorcontrib><creatorcontrib>Zhang, Guanfei</creatorcontrib><creatorcontrib>Pi, Xin</creatorcontrib><creatorcontrib>Long, Jiangang</creatorcontrib><creatorcontrib>Liu, Huadong</creatorcontrib><title>4EBP2-regulated protein translation has a critical role in high-fat diet–induced insulin resistance in hepatocytes</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.</description><subject>4EBP2</subject><subject>Animals</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Line</subject><subject>Diet, High-Fat - adverse effects</subject><subject>hepatocyte</subject><subject>Hepatocytes - metabolism</subject><subject>Insulin - metabolism</subject><subject>insulin resistance</subject><subject>Insulin Resistance - physiology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>palmitic acid</subject><subject>Palmitic Acid - metabolism</subject><subject>Protein Biosynthesis</subject><subject>Proteomics</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi0EotvCA3BBOXLJ1nYSOxYHRKv-QaoEB5C4WRN7sutV1l5sp1JvfQfekCfBVUoFF3wZ2fObbzzzEfKG0TWjTJzu1rvBrDnlTbl3DeuekRWjfVM3Hfv-nKwo5axWvOuPyHFKO1pOq9hLctRIqaSkdEVye3H2hdcRN_MEGW11iCGj81WO4FN5csFXW0gVVCa67AxMVQwTVgXZus22HiFX1mH-df_TeTubIuF8mqeSj5hcyuDNQuMBcjB3GdMr8mKEKeHrx3hCvl1efD2_rm8-X306_3hTm5a2uRYKhOgsMjNSi3ykwG2jcBhAAEppx04h0l6yEUTfiQGoAi5U36NpR9Wa5oR8WHQP87BHa9CXqSZ9iG4P8U4HcPrfjHdbvQm3mlHRMs5lUXj3qBDDjxlT1nuXDE4TeAxz0ryXLRec9rygbEFNDClFHJ_6MKof7NI7XezSD3bpxa5S8_bvDz5V_PGnAO8XAMuabh1GnYzDslHrIpqsbXD_kf8NKoupxg</recordid><startdate>20231101</startdate><enddate>20231101</enddate><creator>Han, Xiao</creator><creator>Yang, Fei</creator><creator>Zhang, Zhengyi</creator><creator>Hou, Zhanwu</creator><creator>Sun, Qiong</creator><creator>Su, Tian</creator><creator>Lv, Weiqiang</creator><creator>Wang, Zhen</creator><creator>Yuan, Chao</creator><creator>Zhang, Guanfei</creator><creator>Pi, Xin</creator><creator>Long, Jiangang</creator><creator>Liu, Huadong</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20231101</creationdate><title>4EBP2-regulated protein translation has a critical role in high-fat diet–induced insulin resistance in hepatocytes</title><author>Han, Xiao ; Yang, Fei ; Zhang, Zhengyi ; Hou, Zhanwu ; Sun, Qiong ; Su, Tian ; Lv, Weiqiang ; Wang, Zhen ; Yuan, Chao ; Zhang, Guanfei ; Pi, Xin ; Long, Jiangang ; Liu, Huadong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-69a665de1cf0de2f0a2d39ebba6ae77df59ee0871fa6856ba09a26988ec4f94c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>4EBP2</topic><topic>Animals</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Line</topic><topic>Diet, High-Fat - adverse effects</topic><topic>hepatocyte</topic><topic>Hepatocytes - metabolism</topic><topic>Insulin - metabolism</topic><topic>insulin resistance</topic><topic>Insulin Resistance - physiology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>palmitic acid</topic><topic>Palmitic Acid - metabolism</topic><topic>Protein Biosynthesis</topic><topic>Proteomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Xiao</creatorcontrib><creatorcontrib>Yang, Fei</creatorcontrib><creatorcontrib>Zhang, Zhengyi</creatorcontrib><creatorcontrib>Hou, Zhanwu</creatorcontrib><creatorcontrib>Sun, Qiong</creatorcontrib><creatorcontrib>Su, Tian</creatorcontrib><creatorcontrib>Lv, Weiqiang</creatorcontrib><creatorcontrib>Wang, Zhen</creatorcontrib><creatorcontrib>Yuan, Chao</creatorcontrib><creatorcontrib>Zhang, Guanfei</creatorcontrib><creatorcontrib>Pi, Xin</creatorcontrib><creatorcontrib>Long, Jiangang</creatorcontrib><creatorcontrib>Liu, Huadong</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Xiao</au><au>Yang, Fei</au><au>Zhang, Zhengyi</au><au>Hou, Zhanwu</au><au>Sun, Qiong</au><au>Su, Tian</au><au>Lv, Weiqiang</au><au>Wang, Zhen</au><au>Yuan, Chao</au><au>Zhang, Guanfei</au><au>Pi, Xin</au><au>Long, Jiangang</au><au>Liu, Huadong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>4EBP2-regulated protein translation has a critical role in high-fat diet–induced insulin resistance in hepatocytes</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2023-11-01</date><risdate>2023</risdate><volume>299</volume><issue>11</issue><spage>105315</spage><epage>105315</epage><pages>105315-105315</pages><artnum>105315</artnum><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>37797700</pmid><doi>10.1016/j.jbc.2023.105315</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | 4EBP2 Animals Carrier Proteins - metabolism Cell Line Diet, High-Fat - adverse effects hepatocyte Hepatocytes - metabolism Insulin - metabolism insulin resistance Insulin Resistance - physiology Male Mice Mice, Inbred C57BL palmitic acid Palmitic Acid - metabolism Protein Biosynthesis Proteomics |
| title | 4EBP2-regulated protein translation has a critical role in high-fat diet–induced insulin resistance in hepatocytes |
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