Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism
Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after m...
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| Veröffentlicht in: | Cell metabolism 2019-11, Vol.30 (5), p.937-951.e5 |
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| creator | Zhang, Xingzhong Zhang, Yangming Wang, Pengcheng Zhang, Song-Yang Dong, Yongqiang Zeng, Guangyi Yan, Yu Sun, Lulu Wu, Qing Liu, Huiying Liu, Bo Kong, Wei Wang, Xian Jiang, Changtao |
| description | Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis. |
| doi_str_mv | 10.1016/j.cmet.2019.09.016 |
| format | Article |
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Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.</description><identifier>ISSN: 1550-4131</identifier><identifier>EISSN: 1932-7420</identifier><identifier>DOI: 10.1016/j.cmet.2019.09.016</identifier><identifier>PMID: 31668872</identifier><language>eng</language><publisher>United States</publisher><subject>Adipocytes - metabolism ; Adipose Tissue - metabolism ; Alkaline Ceramidase - genetics ; Alkaline Ceramidase - metabolism ; Animals ; Atherosclerosis - drug therapy ; Atherosclerosis - etiology ; Atherosclerosis - metabolism ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Basic Helix-Loop-Helix Transcription Factors - metabolism ; Ceramides - metabolism ; Cholesterol - metabolism ; Cold Temperature ; Diet, Western - adverse effects ; Gene Knockout Techniques ; Glycine - analogs & derivatives ; Glycine - pharmacology ; Glycine - therapeutic use ; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors ; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism ; Isoquinolines - pharmacology ; Isoquinolines - therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Signal Transduction - drug effects ; Thermogenesis ; Up-Regulation - genetics</subject><ispartof>Cell metabolism, 2019-11, Vol.30 (5), p.937-951.e5</ispartof><rights>Copyright © 2019 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c347t-bada037011f0deea3472ba73e876194c860abf80941c4e72259afa36f131b5a33</citedby><cites>FETCH-LOGICAL-c347t-bada037011f0deea3472ba73e876194c860abf80941c4e72259afa36f131b5a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31668872$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Xingzhong</creatorcontrib><creatorcontrib>Zhang, Yangming</creatorcontrib><creatorcontrib>Wang, Pengcheng</creatorcontrib><creatorcontrib>Zhang, Song-Yang</creatorcontrib><creatorcontrib>Dong, Yongqiang</creatorcontrib><creatorcontrib>Zeng, Guangyi</creatorcontrib><creatorcontrib>Yan, Yu</creatorcontrib><creatorcontrib>Sun, Lulu</creatorcontrib><creatorcontrib>Wu, Qing</creatorcontrib><creatorcontrib>Liu, Huiying</creatorcontrib><creatorcontrib>Liu, Bo</creatorcontrib><creatorcontrib>Kong, Wei</creatorcontrib><creatorcontrib>Wang, Xian</creatorcontrib><creatorcontrib>Jiang, Changtao</creatorcontrib><title>Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism</title><title>Cell metabolism</title><addtitle>Cell Metab</addtitle><description>Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.</description><subject>Adipocytes - metabolism</subject><subject>Adipose Tissue - metabolism</subject><subject>Alkaline Ceramidase - genetics</subject><subject>Alkaline Ceramidase - metabolism</subject><subject>Animals</subject><subject>Atherosclerosis - drug therapy</subject><subject>Atherosclerosis - etiology</subject><subject>Atherosclerosis - metabolism</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Ceramides - metabolism</subject><subject>Cholesterol - metabolism</subject><subject>Cold Temperature</subject><subject>Diet, Western - adverse effects</subject><subject>Gene Knockout Techniques</subject><subject>Glycine - analogs & derivatives</subject><subject>Glycine - pharmacology</subject><subject>Glycine - therapeutic use</subject><subject>Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors</subject><subject>Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism</subject><subject>Isoquinolines - pharmacology</subject><subject>Isoquinolines - therapeutic use</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout, ApoE</subject><subject>Signal Transduction - drug effects</subject><subject>Thermogenesis</subject><subject>Up-Regulation - genetics</subject><issn>1550-4131</issn><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UNtKw0AUXESxtfoDPsg--pK4l2STPJZibaGgoD4vm82Jbki6cTcB81n-iN9kYqtwOGc4zAzMIHRNSUgJFXdVqBvoQkZoFpJxqDhBc5pxFiQRI6cjjmMSRJTTGbrwviKEC57xczTjVIg0TdgcVcvCtFYPHeDN0NpPo4Ltvui1yWvAa6U76zD7_sLPfds68B48Xnbv4KzX9bSNx_mAn5xtbGf2b_jXzgNegVONKUagOpXb2vjmEp2VqvZwdbwL9Lq-f1ltgt3jw3a13AWaR0kX5KpQhCeE0pIUAGp8slwlHNJE0CzSqSAqL1OSRVRHkDAWZ6pUXJRjzjxWnC_Q7cG3dfajB9_JxngNda32YHsvGackYWnGxEhlB6oeo3gHpWydaZQbJCVy6lhWcupYTh1LMg6dRDdH_z5voPiX_JXKfwA25Xrs</recordid><startdate>20191105</startdate><enddate>20191105</enddate><creator>Zhang, Xingzhong</creator><creator>Zhang, Yangming</creator><creator>Wang, Pengcheng</creator><creator>Zhang, Song-Yang</creator><creator>Dong, Yongqiang</creator><creator>Zeng, Guangyi</creator><creator>Yan, Yu</creator><creator>Sun, Lulu</creator><creator>Wu, Qing</creator><creator>Liu, Huiying</creator><creator>Liu, Bo</creator><creator>Kong, Wei</creator><creator>Wang, Xian</creator><creator>Jiang, Changtao</creator><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></search><sort><creationdate>20191105</creationdate><title>Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism</title><author>Zhang, Xingzhong ; Zhang, Yangming ; Wang, Pengcheng ; Zhang, Song-Yang ; Dong, Yongqiang ; Zeng, Guangyi ; Yan, Yu ; Sun, Lulu ; Wu, Qing ; Liu, Huiying ; Liu, Bo ; Kong, Wei ; Wang, Xian ; Jiang, Changtao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c347t-bada037011f0deea3472ba73e876194c860abf80941c4e72259afa36f131b5a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adipocytes - metabolism</topic><topic>Adipose Tissue - metabolism</topic><topic>Alkaline Ceramidase - genetics</topic><topic>Alkaline Ceramidase - metabolism</topic><topic>Animals</topic><topic>Atherosclerosis - drug therapy</topic><topic>Atherosclerosis - etiology</topic><topic>Atherosclerosis - metabolism</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Ceramides - metabolism</topic><topic>Cholesterol - metabolism</topic><topic>Cold Temperature</topic><topic>Diet, Western - adverse effects</topic><topic>Gene Knockout Techniques</topic><topic>Glycine - analogs & derivatives</topic><topic>Glycine - pharmacology</topic><topic>Glycine - therapeutic use</topic><topic>Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors</topic><topic>Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism</topic><topic>Isoquinolines - pharmacology</topic><topic>Isoquinolines - therapeutic use</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout, ApoE</topic><topic>Signal Transduction - drug effects</topic><topic>Thermogenesis</topic><topic>Up-Regulation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Xingzhong</creatorcontrib><creatorcontrib>Zhang, Yangming</creatorcontrib><creatorcontrib>Wang, Pengcheng</creatorcontrib><creatorcontrib>Zhang, Song-Yang</creatorcontrib><creatorcontrib>Dong, Yongqiang</creatorcontrib><creatorcontrib>Zeng, Guangyi</creatorcontrib><creatorcontrib>Yan, Yu</creatorcontrib><creatorcontrib>Sun, Lulu</creatorcontrib><creatorcontrib>Wu, Qing</creatorcontrib><creatorcontrib>Liu, Huiying</creatorcontrib><creatorcontrib>Liu, Bo</creatorcontrib><creatorcontrib>Kong, Wei</creatorcontrib><creatorcontrib>Wang, Xian</creatorcontrib><creatorcontrib>Jiang, Changtao</creatorcontrib><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><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Xingzhong</au><au>Zhang, Yangming</au><au>Wang, Pengcheng</au><au>Zhang, Song-Yang</au><au>Dong, Yongqiang</au><au>Zeng, Guangyi</au><au>Yan, Yu</au><au>Sun, Lulu</au><au>Wu, Qing</au><au>Liu, Huiying</au><au>Liu, Bo</au><au>Kong, Wei</au><au>Wang, Xian</au><au>Jiang, Changtao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2019-11-05</date><risdate>2019</risdate><volume>30</volume><issue>5</issue><spage>937</spage><epage>951.e5</epage><pages>937-951.e5</pages><issn>1550-4131</issn><eissn>1932-7420</eissn><abstract>Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.</abstract><cop>United States</cop><pmid>31668872</pmid><doi>10.1016/j.cmet.2019.09.016</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell metabolism, 2019-11, Vol.30 (5), p.937-951.e5 |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adipocytes - metabolism Adipose Tissue - metabolism Alkaline Ceramidase - genetics Alkaline Ceramidase - metabolism Animals Atherosclerosis - drug therapy Atherosclerosis - etiology Atherosclerosis - metabolism Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Ceramides - metabolism Cholesterol - metabolism Cold Temperature Diet, Western - adverse effects Gene Knockout Techniques Glycine - analogs & derivatives Glycine - pharmacology Glycine - therapeutic use Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism Isoquinolines - pharmacology Isoquinolines - therapeutic use Mice Mice, Inbred C57BL Mice, Knockout, ApoE Signal Transduction - drug effects Thermogenesis Up-Regulation - genetics |
| title | Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism |
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