Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostas...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2017-06, Vol.65 (6), p.1936-1947 |
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| container_end_page | 1947 |
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| container_issue | 6 |
| container_start_page | 1936 |
| container_title | Hepatology (Baltimore, Md.) |
| container_volume | 65 |
| creator | Li, Na Zhou, Zhang‐Sen Shen, Yang Xu, Jie Miao, Hong‐Hua Xiong, Ying Xu, Feng Li, Bo‐Liang Luo, Jie Song, Bao‐Liang |
| description | Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78‐kDa cell‐surface glycoprotein or SREBP cleavage‐activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine‐induced HCC progression by down‐regulating tumor‐promoting cytokines, including interleukin (IL)‐6, tumor necrosis factor alpha, and IL‐1β. Conclusion: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936‐1947). |
| doi_str_mv | 10.1002/hep.29018 |
| format | Article |
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However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78‐kDa cell‐surface glycoprotein or SREBP cleavage‐activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine‐induced HCC progression by down‐regulating tumor‐promoting cytokines, including interleukin (IL)‐6, tumor necrosis factor alpha, and IL‐1β. Conclusion: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936‐1947).</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.29018</identifier><identifier>PMID: 28027595</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Animals ; Biosynthesis ; Carcinogenesis - pathology ; Carcinoma, Hepatocellular - pathology ; Carcinoma, Hepatocellular - physiopathology ; Cell surface ; Diethylnitrosamine ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; Hepatocellular carcinoma ; Hepatocytes ; Hepatocytes - metabolism ; Hepatocytes - pathology ; Hepatology ; Homeostasis ; Inflammation - pathology ; Inflammation - prevention & control ; Interleukin 1 ; Interleukin-1beta - metabolism ; Lipids ; Liver cancer ; Liver Neoplasms - pathology ; Liver Neoplasms - physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms, Experimental ; Obesity - complications ; Obesity - pathology ; Protein Binding - genetics ; Proteins ; Random Allocation ; Real-Time Polymerase Chain Reaction - methods ; Reference Values ; Risk Factors ; Sterol Regulatory Element Binding Protein 1 - genetics ; Sterol regulatory element-binding protein ; Sterols ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α</subject><ispartof>Hepatology (Baltimore, Md.), 2017-06, Vol.65 (6), p.1936-1947</ispartof><rights>2016 by the American Association for the Study of Liver Diseases.</rights><rights>2017 by the American Association for the Study of Liver Diseases</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4198-bc23a73bc61e7e6b99c14e49ab94c89258b2cabd4add6bc3b256f1a2dd5560803</citedby><cites>FETCH-LOGICAL-c4198-bc23a73bc61e7e6b99c14e49ab94c89258b2cabd4add6bc3b256f1a2dd5560803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.29018$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.29018$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28027595$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Na</creatorcontrib><creatorcontrib>Zhou, Zhang‐Sen</creatorcontrib><creatorcontrib>Shen, Yang</creatorcontrib><creatorcontrib>Xu, Jie</creatorcontrib><creatorcontrib>Miao, Hong‐Hua</creatorcontrib><creatorcontrib>Xiong, Ying</creatorcontrib><creatorcontrib>Xu, Feng</creatorcontrib><creatorcontrib>Li, Bo‐Liang</creatorcontrib><creatorcontrib>Luo, Jie</creatorcontrib><creatorcontrib>Song, Bao‐Liang</creatorcontrib><title>Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78‐kDa cell‐surface glycoprotein or SREBP cleavage‐activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine‐induced HCC progression by down‐regulating tumor‐promoting cytokines, including interleukin (IL)‐6, tumor necrosis factor alpha, and IL‐1β. Conclusion: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936‐1947).</description><subject>Animals</subject><subject>Biosynthesis</subject><subject>Carcinogenesis - pathology</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Carcinoma, Hepatocellular - physiopathology</subject><subject>Cell surface</subject><subject>Diethylnitrosamine</subject><subject>Disease Models, Animal</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - pathology</subject><subject>Hepatology</subject><subject>Homeostasis</subject><subject>Inflammation - pathology</subject><subject>Inflammation - prevention & control</subject><subject>Interleukin 1</subject><subject>Interleukin-1beta - metabolism</subject><subject>Lipids</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - pathology</subject><subject>Liver Neoplasms - physiopathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Neoplasms, Experimental</subject><subject>Obesity - complications</subject><subject>Obesity - pathology</subject><subject>Protein Binding - genetics</subject><subject>Proteins</subject><subject>Random Allocation</subject><subject>Real-Time Polymerase Chain Reaction - methods</subject><subject>Reference Values</subject><subject>Risk Factors</subject><subject>Sterol Regulatory Element Binding Protein 1 - genetics</subject><subject>Sterol regulatory element-binding protein</subject><subject>Sterols</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kb1u1TAYhi1ERQ-FgRtAllhgSOvfxB5RVWilSu1Q5sh2vvS4SuxgJ6qy9QIYuEauBJ9zCgMSkwc_3-PX34vQO0pOKSHsbAvTKdOEqhdoQyVrKs4leYk2hDWk0pTrY_Q65wdCiBZMvULHTJUrqeUG_bgKW2_97GPAscfzFnCeIcUBJ7hfBjPHtGIYYIQw_3r6aX3ofLjHU4oz-IAnM28fzYrzMk0JcoaMS5gy5WAYynjCziTnQxwNtmtx7qmdwYd-MONo9i8X0-gdvEFHvRkyvH0-T9C3Lxd355fV9c3Xq_PP15UTVKvKOsZNw62rKTRQW60dFSC0sVo4pZlUljljO2G6rraOWybrnhrWdVLWRBF-gj4evOUb3xfIczv6vEtsAsQlt1RJ3gihOC_oh3_Qh7ikUNK1tGxcSEJ1XahPB8qlmHOCvp2SH01aW0raXUVt2Uq7r6iw75-Nix2h-0v-6aQAZwfg0Q-w_t_UXl7cHpS_AaeJn5o</recordid><startdate>201706</startdate><enddate>201706</enddate><creator>Li, Na</creator><creator>Zhou, Zhang‐Sen</creator><creator>Shen, Yang</creator><creator>Xu, Jie</creator><creator>Miao, Hong‐Hua</creator><creator>Xiong, Ying</creator><creator>Xu, Feng</creator><creator>Li, Bo‐Liang</creator><creator>Luo, Jie</creator><creator>Song, Bao‐Liang</creator><general>Wolters Kluwer Health, Inc</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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201706</creationdate><title>Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice</title><author>Li, Na ; Zhou, Zhang‐Sen ; Shen, Yang ; Xu, Jie ; Miao, Hong‐Hua ; Xiong, Ying ; Xu, Feng ; Li, Bo‐Liang ; Luo, Jie ; Song, Bao‐Liang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4198-bc23a73bc61e7e6b99c14e49ab94c89258b2cabd4add6bc3b256f1a2dd5560803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Biosynthesis</topic><topic>Carcinogenesis - pathology</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Carcinoma, Hepatocellular - physiopathology</topic><topic>Cell surface</topic><topic>Diethylnitrosamine</topic><topic>Disease Models, Animal</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>Hepatocytes - pathology</topic><topic>Hepatology</topic><topic>Homeostasis</topic><topic>Inflammation - pathology</topic><topic>Inflammation - prevention & control</topic><topic>Interleukin 1</topic><topic>Interleukin-1beta - metabolism</topic><topic>Lipids</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - pathology</topic><topic>Liver Neoplasms - physiopathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Neoplasms, Experimental</topic><topic>Obesity - complications</topic><topic>Obesity - pathology</topic><topic>Protein Binding - genetics</topic><topic>Proteins</topic><topic>Random Allocation</topic><topic>Real-Time Polymerase Chain Reaction - methods</topic><topic>Reference Values</topic><topic>Risk Factors</topic><topic>Sterol Regulatory Element Binding Protein 1 - genetics</topic><topic>Sterol regulatory element-binding protein</topic><topic>Sterols</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Na</creatorcontrib><creatorcontrib>Zhou, Zhang‐Sen</creatorcontrib><creatorcontrib>Shen, Yang</creatorcontrib><creatorcontrib>Xu, Jie</creatorcontrib><creatorcontrib>Miao, Hong‐Hua</creatorcontrib><creatorcontrib>Xiong, Ying</creatorcontrib><creatorcontrib>Xu, Feng</creatorcontrib><creatorcontrib>Li, Bo‐Liang</creatorcontrib><creatorcontrib>Luo, Jie</creatorcontrib><creatorcontrib>Song, Bao‐Liang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Na</au><au>Zhou, Zhang‐Sen</au><au>Shen, Yang</au><au>Xu, Jie</au><au>Miao, Hong‐Hua</au><au>Xiong, Ying</au><au>Xu, Feng</au><au>Li, Bo‐Liang</au><au>Luo, Jie</au><au>Song, Bao‐Liang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2017-06</date><risdate>2017</risdate><volume>65</volume><issue>6</issue><spage>1936</spage><epage>1947</epage><pages>1936-1947</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><abstract>Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78‐kDa cell‐surface glycoprotein or SREBP cleavage‐activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine‐induced HCC progression by down‐regulating tumor‐promoting cytokines, including interleukin (IL)‐6, tumor necrosis factor alpha, and IL‐1β. Conclusion: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936‐1947).</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>28027595</pmid><doi>10.1002/hep.29018</doi><tpages>12</tpages></addata></record> |
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| subjects | Animals Biosynthesis Carcinogenesis - pathology Carcinoma, Hepatocellular - pathology Carcinoma, Hepatocellular - physiopathology Cell surface Diethylnitrosamine Disease Models, Animal Gene Expression Regulation, Neoplastic Hepatocellular carcinoma Hepatocytes Hepatocytes - metabolism Hepatocytes - pathology Hepatology Homeostasis Inflammation - pathology Inflammation - prevention & control Interleukin 1 Interleukin-1beta - metabolism Lipids Liver cancer Liver Neoplasms - pathology Liver Neoplasms - physiopathology Male Mice Mice, Inbred C57BL Mice, Knockout Neoplasms, Experimental Obesity - complications Obesity - pathology Protein Binding - genetics Proteins Random Allocation Real-Time Polymerase Chain Reaction - methods Reference Values Risk Factors Sterol Regulatory Element Binding Protein 1 - genetics Sterol regulatory element-binding protein Sterols Tumor Cells, Cultured Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α |
| title | Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice |
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