On the regulatory importance of 27-hydroxycholesterol in mouse liver
•Under basal conditions 27-hydroxycholesterol has little regulatory effects.•27-Hydroxycholesterol mediates effect of dietary cholesterol on some LXR target genes.•Thee above effects of 27-hydroxycholesterol are not always seen at the protein level. 27-Hydroxycholesterol (27OH) is a strong suppresso...
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| Veröffentlicht in: | The Journal of steroid biochemistry and molecular biology 2017-05, Vol.169, p.10-21 |
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| creator | Heverin, Maura Ali, Zeina Olin, Maria Tillander, Veronika Joibari, Masoumeh Motamedi Makoveichuk, Elena Leitersdorf, Eran Warner, Margret Olivercrona, Gunilla Gustafsson, Jan-Åke Björkhem, Ingemar |
| description | •Under basal conditions 27-hydroxycholesterol has little regulatory effects.•27-Hydroxycholesterol mediates effect of dietary cholesterol on some LXR target genes.•Thee above effects of 27-hydroxycholesterol are not always seen at the protein level.
27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial.
Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes.
In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73–79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl).
The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions. |
| doi_str_mv | 10.1016/j.jsbmb.2016.02.001 |
| format | Article |
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27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial.
Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes.
In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73–79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl).
The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.</description><identifier>ISSN: 0960-0760</identifier><identifier>ISSN: 1879-1220</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/j.jsbmb.2016.02.001</identifier><identifier>PMID: 26851362</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ABCA1 protein ; Abcg8 ; Animals ; ATP Binding Cassette Transporter, Subfamily G, Member 8 - metabolism ; ATP-binding protein ; Biosynthesis ; Cholestanetriol 26-Monooxygenase - genetics ; Cholesterol ; Cholesterol metabolism ; Cholic acid ; Cyp27-/- mice ; Cytochrome P-450 ; Cytochrome P450 Family 7 - genetics ; Effects ; Gene expression ; Gene Expression Profiling ; Genes ; Hydroxycholesterols - metabolism ; Lipoprotein lipase ; Lipoprotein Lipase - metabolism ; Lipoproteins - metabolism ; Liver ; Liver - metabolism ; Liver X Receptors - metabolism ; Lxr ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear receptor ; OXysterols ; Receptors, Cytoplasmic and Nuclear - metabolism ; Srebp1c ; Steroid Hydroxylases - genetics ; Sterol Regulatory Element Binding Protein 1 - metabolism ; Sterol regulatory element-binding protein ; Studies ; Transcription ; Transcription, Genetic ; Transgenic mice</subject><ispartof>The Journal of steroid biochemistry and molecular biology, 2017-05, Vol.169, p.10-21</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier BV May 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-4199e8057adf9e72b2dd8e39b3dc30753ed2247d34b36e8755799ab71d1fd6133</citedby><cites>FETCH-LOGICAL-c529t-4199e8057adf9e72b2dd8e39b3dc30753ed2247d34b36e8755799ab71d1fd6133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960076016300152$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26851362$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-136070$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:135815818$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Heverin, Maura</creatorcontrib><creatorcontrib>Ali, Zeina</creatorcontrib><creatorcontrib>Olin, Maria</creatorcontrib><creatorcontrib>Tillander, Veronika</creatorcontrib><creatorcontrib>Joibari, Masoumeh Motamedi</creatorcontrib><creatorcontrib>Makoveichuk, Elena</creatorcontrib><creatorcontrib>Leitersdorf, Eran</creatorcontrib><creatorcontrib>Warner, Margret</creatorcontrib><creatorcontrib>Olivercrona, Gunilla</creatorcontrib><creatorcontrib>Gustafsson, Jan-Åke</creatorcontrib><creatorcontrib>Björkhem, Ingemar</creatorcontrib><title>On the regulatory importance of 27-hydroxycholesterol in mouse liver</title><title>The Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>•Under basal conditions 27-hydroxycholesterol has little regulatory effects.•27-Hydroxycholesterol mediates effect of dietary cholesterol on some LXR target genes.•Thee above effects of 27-hydroxycholesterol are not always seen at the protein level.
27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial.
Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes.
In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73–79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl).
The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.</description><subject>ABCA1 protein</subject><subject>Abcg8</subject><subject>Animals</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 8 - metabolism</subject><subject>ATP-binding protein</subject><subject>Biosynthesis</subject><subject>Cholestanetriol 26-Monooxygenase - genetics</subject><subject>Cholesterol</subject><subject>Cholesterol metabolism</subject><subject>Cholic acid</subject><subject>Cyp27-/- mice</subject><subject>Cytochrome P-450</subject><subject>Cytochrome P450 Family 7 - genetics</subject><subject>Effects</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genes</subject><subject>Hydroxycholesterols - metabolism</subject><subject>Lipoprotein lipase</subject><subject>Lipoprotein Lipase - metabolism</subject><subject>Lipoproteins - metabolism</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver X Receptors - metabolism</subject><subject>Lxr</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nuclear receptor</subject><subject>OXysterols</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Srebp1c</subject><subject>Steroid Hydroxylases - genetics</subject><subject>Sterol Regulatory Element Binding Protein 1 - metabolism</subject><subject>Sterol regulatory element-binding protein</subject><subject>Studies</subject><subject>Transcription</subject><subject>Transcription, Genetic</subject><subject>Transgenic mice</subject><issn>0960-0760</issn><issn>1879-1220</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0EokvhFyChSFy4JIztxI4PHKqWL6lSL8B1lMSTrkMSL3bSsv8eL7v0wKEnf-iZd-adl7HXHAoOXL0fiiG2U1uI9ChAFAD8CdvwWpucCwFP2QaMghy0gjP2IsYBAKTk-jk7E6quuFRiw65u5mzZUhbodh2bxYd95qadD0szd5T5PhM63-5t8L_33daPFBcKfszcnE1-jZSN7o7CS_asb8ZIr07nOfv-6eO3yy_59c3nr5cX13lXCbPkJTeGaqh0Y3tDWrTC2pqkaaXtJOhKkhWi1FaWrVRU66rSxjSt5pb3VnEpz1l-1I33tFtb3AU3NWGPvnF4-vqZboQV6LIUj_JX7scF-nCL67Ri2gVoSPy7I78L_teavOLkYkfj2MyU3CKvhVIV1-Iwytv_0MGvYU7ukRttylInyUTJI9UFH2Og_mEEDngIEQf8GyIeQkQQmEJMVW9O2ms7kX2o-ZdaAj4cAUrLvnMUMHaOUmDWBeoWtN492uAPV7utmQ</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Heverin, Maura</creator><creator>Ali, Zeina</creator><creator>Olin, Maria</creator><creator>Tillander, Veronika</creator><creator>Joibari, Masoumeh Motamedi</creator><creator>Makoveichuk, Elena</creator><creator>Leitersdorf, Eran</creator><creator>Warner, Margret</creator><creator>Olivercrona, Gunilla</creator><creator>Gustafsson, Jan-Åke</creator><creator>Björkhem, Ingemar</creator><general>Elsevier Ltd</general><general>Elsevier BV</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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D93</scope></search><sort><creationdate>20170501</creationdate><title>On the regulatory importance of 27-hydroxycholesterol in mouse liver</title><author>Heverin, Maura ; Ali, Zeina ; Olin, Maria ; Tillander, Veronika ; Joibari, Masoumeh Motamedi ; Makoveichuk, Elena ; Leitersdorf, Eran ; Warner, Margret ; Olivercrona, Gunilla ; Gustafsson, Jan-Åke ; Björkhem, Ingemar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-4199e8057adf9e72b2dd8e39b3dc30753ed2247d34b36e8755799ab71d1fd6133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>ABCA1 protein</topic><topic>Abcg8</topic><topic>Animals</topic><topic>ATP Binding Cassette Transporter, Subfamily G, Member 8 - metabolism</topic><topic>ATP-binding protein</topic><topic>Biosynthesis</topic><topic>Cholestanetriol 26-Monooxygenase - genetics</topic><topic>Cholesterol</topic><topic>Cholesterol metabolism</topic><topic>Cholic acid</topic><topic>Cyp27-/- mice</topic><topic>Cytochrome P-450</topic><topic>Cytochrome P450 Family 7 - genetics</topic><topic>Effects</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Genes</topic><topic>Hydroxycholesterols - metabolism</topic><topic>Lipoprotein lipase</topic><topic>Lipoprotein Lipase - metabolism</topic><topic>Lipoproteins - metabolism</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver X Receptors - metabolism</topic><topic>Lxr</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Nuclear receptor</topic><topic>OXysterols</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Srebp1c</topic><topic>Steroid Hydroxylases - genetics</topic><topic>Sterol Regulatory Element Binding Protein 1 - metabolism</topic><topic>Sterol regulatory element-binding protein</topic><topic>Studies</topic><topic>Transcription</topic><topic>Transcription, Genetic</topic><topic>Transgenic mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heverin, Maura</creatorcontrib><creatorcontrib>Ali, Zeina</creatorcontrib><creatorcontrib>Olin, Maria</creatorcontrib><creatorcontrib>Tillander, Veronika</creatorcontrib><creatorcontrib>Joibari, Masoumeh Motamedi</creatorcontrib><creatorcontrib>Makoveichuk, Elena</creatorcontrib><creatorcontrib>Leitersdorf, Eran</creatorcontrib><creatorcontrib>Warner, Margret</creatorcontrib><creatorcontrib>Olivercrona, Gunilla</creatorcontrib><creatorcontrib>Gustafsson, Jan-Åke</creatorcontrib><creatorcontrib>Björkhem, Ingemar</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Umeå universitet</collection><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heverin, Maura</au><au>Ali, Zeina</au><au>Olin, Maria</au><au>Tillander, Veronika</au><au>Joibari, Masoumeh Motamedi</au><au>Makoveichuk, Elena</au><au>Leitersdorf, Eran</au><au>Warner, Margret</au><au>Olivercrona, Gunilla</au><au>Gustafsson, Jan-Åke</au><au>Björkhem, Ingemar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>On the regulatory importance of 27-hydroxycholesterol in mouse liver</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>169</volume><spage>10</spage><epage>21</epage><pages>10-21</pages><issn>0960-0760</issn><issn>1879-1220</issn><eissn>1879-1220</eissn><abstract>•Under basal conditions 27-hydroxycholesterol has little regulatory effects.•27-Hydroxycholesterol mediates effect of dietary cholesterol on some LXR target genes.•Thee above effects of 27-hydroxycholesterol are not always seen at the protein level.
27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial.
Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes.
In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73–79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl).
The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26851362</pmid><doi>10.1016/j.jsbmb.2016.02.001</doi><tpages>12</tpages></addata></record> |
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| subjects | ABCA1 protein Abcg8 Animals ATP Binding Cassette Transporter, Subfamily G, Member 8 - metabolism ATP-binding protein Biosynthesis Cholestanetriol 26-Monooxygenase - genetics Cholesterol Cholesterol metabolism Cholic acid Cyp27-/- mice Cytochrome P-450 Cytochrome P450 Family 7 - genetics Effects Gene expression Gene Expression Profiling Genes Hydroxycholesterols - metabolism Lipoprotein lipase Lipoprotein Lipase - metabolism Lipoproteins - metabolism Liver Liver - metabolism Liver X Receptors - metabolism Lxr Male Mice Mice, Inbred C57BL Mice, Knockout Nuclear receptor OXysterols Receptors, Cytoplasmic and Nuclear - metabolism Srebp1c Steroid Hydroxylases - genetics Sterol Regulatory Element Binding Protein 1 - metabolism Sterol regulatory element-binding protein Studies Transcription Transcription, Genetic Transgenic mice |
| title | On the regulatory importance of 27-hydroxycholesterol in mouse liver |
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