2H2O-Based High-Density Lipoprotein Turnover Method for the Assessment of Dynamic High-Density Lipoprotein Function in Mice
OBJECTIVE—High-density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver for clearance. Reduced HDL-cholesterol (HDLc) is associated with atherosclerosis; however, as a predictor of cardiovascular disease, HDLc has limitations because it is not a direct ma...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2013-08, Vol.33 (8), p.1994-2003 |
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| container_title | Arteriosclerosis, thrombosis, and vascular biology |
| container_volume | 33 |
| creator | Kasumov, Takhar Willard, Belinda Li, Ling Li, Min Conger, Heather Buffa, Jennifer A Previs, Stephen McCullough, Arthur Hazen, Stanley L Smith, Jonathan D |
| description | OBJECTIVE—High-density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver for clearance. Reduced HDL-cholesterol (HDLc) is associated with atherosclerosis; however, as a predictor of cardiovascular disease, HDLc has limitations because it is not a direct marker of HDL functionality. Our objective was to develop a mass spectrometry–based method for the simultaneous measurement of HDLc and ApoAI kinetics in mice, using a single H2O tracer, and use it to examine genetic and drug perturbations on HDL turnover in vivo.
APPROACH AND RESULTS—Mice were given H2O in the drinking water, and serial blood samples were collected at different time points. HDLc and ApoAI gradually incorporated H, allowing experimental measurement of fractional catabolic rates and production rates for HDLc and ApoAI. ApoE mice displayed increased fractional catabolic rates (P |
| doi_str_mv | 10.1161/ATVBAHA.113.301700 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_wolte</sourceid><recordid>TN_cdi_pubmed_primary_23766259</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>23766259</sourcerecordid><originalsourceid>FETCH-LOGICAL-j2540-7c1c9d9eebd8ec3020d0c90635b2e25ed9e2e8622fdf320fe2aeed49611daea73</originalsourceid><addsrcrecordid>eNp1kMFOg0AYhDdGY7X6Ah7MvgB1919YypG2Vkza9FK9ki37I1RgCbvYNL68mNajp5nJTObwEfLA2YRzyZ_i7fssTuIhiIlgPGTsgtzwAHzPl0JeDp6FkRdIH0bk1to9Y8wHYNdkBCKUEoLohnxDAhtvpixqmpQfhbfAxpbuSFdla9rOOCwbuu27xnxhR9foCqNpbjrqCqSxtWhtjY2jJqeLY6PqMvv_Ztk3mStNQwe_LjO8I1e5qizen3VM3pbP23nirTYvr_N45e0h8JkXZjyLdIS401PMBAOmWRYxKYIdIAQ4VIBTCZDrXADLERSi9iPJuVaoQjEmj6fftt_VqNO2K2vVHdM_CsNAngYHUzns7GfVH7BLC1SVK1LO0l_c6Rn3EER6wi1-ADL8cr0</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>2H2O-Based High-Density Lipoprotein Turnover Method for the Assessment of Dynamic High-Density Lipoprotein Function in Mice</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><source>Journals@Ovid Complete</source><creator>Kasumov, Takhar ; Willard, Belinda ; Li, Ling ; Li, Min ; Conger, Heather ; Buffa, Jennifer A ; Previs, Stephen ; McCullough, Arthur ; Hazen, Stanley L ; Smith, Jonathan D</creator><creatorcontrib>Kasumov, Takhar ; Willard, Belinda ; Li, Ling ; Li, Min ; Conger, Heather ; Buffa, Jennifer A ; Previs, Stephen ; McCullough, Arthur ; Hazen, Stanley L ; Smith, Jonathan D</creatorcontrib><description>OBJECTIVE—High-density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver for clearance. Reduced HDL-cholesterol (HDLc) is associated with atherosclerosis; however, as a predictor of cardiovascular disease, HDLc has limitations because it is not a direct marker of HDL functionality. Our objective was to develop a mass spectrometry–based method for the simultaneous measurement of HDLc and ApoAI kinetics in mice, using a single H2O tracer, and use it to examine genetic and drug perturbations on HDL turnover in vivo.
APPROACH AND RESULTS—Mice were given H2O in the drinking water, and serial blood samples were collected at different time points. HDLc and ApoAI gradually incorporated H, allowing experimental measurement of fractional catabolic rates and production rates for HDLc and ApoAI. ApoE mice displayed increased fractional catabolic rates (P<0.01) and reduced production rates of both HDLc and ApoAI (P<0.05) compared with controls. In human ApoAI transgenic mice, levels and production rates of HDLc and human ApoAI were strikingly higher than in wild-type mice. Myriocin, an inhibitor of sphingolipid synthesis, significantly increased both HDL flux and macrophage-to-feces reverse cholesterol transport, indicating compatibility of this HDL turnover method with the macrophage-specific reverse cholesterol transport assay.
CONCLUSIONS—H2O-labeling can be used to measure HDLc and ApoAI flux in vivo, and to assess the role of genetic and pharmacological interventions on HDL turnover in mice. Safety, simplicity, and low cost of the H2O-based HDL turnover approach suggest that this assay can be scaled for human use to study effects of HDL targeted therapies on dynamic HDL function.</description><identifier>ISSN: 1079-5642</identifier><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/ATVBAHA.113.301700</identifier><identifier>PMID: 23766259</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Animals ; Apolipoprotein A-I - metabolism ; Apolipoproteins E - genetics ; Atherosclerosis - metabolism ; Cholesterol - metabolism ; Deuterium - pharmacokinetics ; Drinking - physiology ; Fatty Acids, Monounsaturated - pharmacology ; Female ; Humans ; Immunosuppressive Agents - pharmacology ; Lipoproteins, HDL - metabolism ; Liver - metabolism ; Macrophages - metabolism ; Male ; Mass Spectrometry - methods ; Mass Spectrometry - standards ; Mice ; Mice, Transgenic ; Water - metabolism</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2013-08, Vol.33 (8), p.1994-2003</ispartof><rights>2013 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23766259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kasumov, Takhar</creatorcontrib><creatorcontrib>Willard, Belinda</creatorcontrib><creatorcontrib>Li, Ling</creatorcontrib><creatorcontrib>Li, Min</creatorcontrib><creatorcontrib>Conger, Heather</creatorcontrib><creatorcontrib>Buffa, Jennifer A</creatorcontrib><creatorcontrib>Previs, Stephen</creatorcontrib><creatorcontrib>McCullough, Arthur</creatorcontrib><creatorcontrib>Hazen, Stanley L</creatorcontrib><creatorcontrib>Smith, Jonathan D</creatorcontrib><title>2H2O-Based High-Density Lipoprotein Turnover Method for the Assessment of Dynamic High-Density Lipoprotein Function in Mice</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description>OBJECTIVE—High-density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver for clearance. Reduced HDL-cholesterol (HDLc) is associated with atherosclerosis; however, as a predictor of cardiovascular disease, HDLc has limitations because it is not a direct marker of HDL functionality. Our objective was to develop a mass spectrometry–based method for the simultaneous measurement of HDLc and ApoAI kinetics in mice, using a single H2O tracer, and use it to examine genetic and drug perturbations on HDL turnover in vivo.
APPROACH AND RESULTS—Mice were given H2O in the drinking water, and serial blood samples were collected at different time points. HDLc and ApoAI gradually incorporated H, allowing experimental measurement of fractional catabolic rates and production rates for HDLc and ApoAI. ApoE mice displayed increased fractional catabolic rates (P<0.01) and reduced production rates of both HDLc and ApoAI (P<0.05) compared with controls. In human ApoAI transgenic mice, levels and production rates of HDLc and human ApoAI were strikingly higher than in wild-type mice. Myriocin, an inhibitor of sphingolipid synthesis, significantly increased both HDL flux and macrophage-to-feces reverse cholesterol transport, indicating compatibility of this HDL turnover method with the macrophage-specific reverse cholesterol transport assay.
CONCLUSIONS—H2O-labeling can be used to measure HDLc and ApoAI flux in vivo, and to assess the role of genetic and pharmacological interventions on HDL turnover in mice. Safety, simplicity, and low cost of the H2O-based HDL turnover approach suggest that this assay can be scaled for human use to study effects of HDL targeted therapies on dynamic HDL function.</description><subject>Animals</subject><subject>Apolipoprotein A-I - metabolism</subject><subject>Apolipoproteins E - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Cholesterol - metabolism</subject><subject>Deuterium - pharmacokinetics</subject><subject>Drinking - physiology</subject><subject>Fatty Acids, Monounsaturated - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Lipoproteins, HDL - metabolism</subject><subject>Liver - metabolism</subject><subject>Macrophages - metabolism</subject><subject>Male</subject><subject>Mass Spectrometry - methods</subject><subject>Mass Spectrometry - standards</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Water - metabolism</subject><issn>1079-5642</issn><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMFOg0AYhDdGY7X6Ah7MvgB1919YypG2Vkza9FK9ki37I1RgCbvYNL68mNajp5nJTObwEfLA2YRzyZ_i7fssTuIhiIlgPGTsgtzwAHzPl0JeDp6FkRdIH0bk1to9Y8wHYNdkBCKUEoLohnxDAhtvpixqmpQfhbfAxpbuSFdla9rOOCwbuu27xnxhR9foCqNpbjrqCqSxtWhtjY2jJqeLY6PqMvv_Ztk3mStNQwe_LjO8I1e5qizen3VM3pbP23nirTYvr_N45e0h8JkXZjyLdIS401PMBAOmWRYxKYIdIAQ4VIBTCZDrXADLERSi9iPJuVaoQjEmj6fftt_VqNO2K2vVHdM_CsNAngYHUzns7GfVH7BLC1SVK1LO0l_c6Rn3EER6wi1-ADL8cr0</recordid><startdate>201308</startdate><enddate>201308</enddate><creator>Kasumov, Takhar</creator><creator>Willard, Belinda</creator><creator>Li, Ling</creator><creator>Li, Min</creator><creator>Conger, Heather</creator><creator>Buffa, Jennifer A</creator><creator>Previs, Stephen</creator><creator>McCullough, Arthur</creator><creator>Hazen, Stanley L</creator><creator>Smith, Jonathan D</creator><general>American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>201308</creationdate><title>2H2O-Based High-Density Lipoprotein Turnover Method for the Assessment of Dynamic High-Density Lipoprotein Function in Mice</title><author>Kasumov, Takhar ; Willard, Belinda ; Li, Ling ; Li, Min ; Conger, Heather ; Buffa, Jennifer A ; Previs, Stephen ; McCullough, Arthur ; Hazen, Stanley L ; Smith, Jonathan D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j2540-7c1c9d9eebd8ec3020d0c90635b2e25ed9e2e8622fdf320fe2aeed49611daea73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Apolipoprotein A-I - metabolism</topic><topic>Apolipoproteins E - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Cholesterol - metabolism</topic><topic>Deuterium - pharmacokinetics</topic><topic>Drinking - physiology</topic><topic>Fatty Acids, Monounsaturated - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>Lipoproteins, HDL - metabolism</topic><topic>Liver - metabolism</topic><topic>Macrophages - metabolism</topic><topic>Male</topic><topic>Mass Spectrometry - methods</topic><topic>Mass Spectrometry - standards</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Water - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kasumov, Takhar</creatorcontrib><creatorcontrib>Willard, Belinda</creatorcontrib><creatorcontrib>Li, Ling</creatorcontrib><creatorcontrib>Li, Min</creatorcontrib><creatorcontrib>Conger, Heather</creatorcontrib><creatorcontrib>Buffa, Jennifer A</creatorcontrib><creatorcontrib>Previs, Stephen</creatorcontrib><creatorcontrib>McCullough, Arthur</creatorcontrib><creatorcontrib>Hazen, Stanley L</creatorcontrib><creatorcontrib>Smith, Jonathan D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kasumov, Takhar</au><au>Willard, Belinda</au><au>Li, Ling</au><au>Li, Min</au><au>Conger, Heather</au><au>Buffa, Jennifer A</au><au>Previs, Stephen</au><au>McCullough, Arthur</au><au>Hazen, Stanley L</au><au>Smith, Jonathan D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2H2O-Based High-Density Lipoprotein Turnover Method for the Assessment of Dynamic High-Density Lipoprotein Function in Mice</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2013-08</date><risdate>2013</risdate><volume>33</volume><issue>8</issue><spage>1994</spage><epage>2003</epage><pages>1994-2003</pages><issn>1079-5642</issn><eissn>1524-4636</eissn><abstract>OBJECTIVE—High-density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver for clearance. Reduced HDL-cholesterol (HDLc) is associated with atherosclerosis; however, as a predictor of cardiovascular disease, HDLc has limitations because it is not a direct marker of HDL functionality. Our objective was to develop a mass spectrometry–based method for the simultaneous measurement of HDLc and ApoAI kinetics in mice, using a single H2O tracer, and use it to examine genetic and drug perturbations on HDL turnover in vivo.
APPROACH AND RESULTS—Mice were given H2O in the drinking water, and serial blood samples were collected at different time points. HDLc and ApoAI gradually incorporated H, allowing experimental measurement of fractional catabolic rates and production rates for HDLc and ApoAI. ApoE mice displayed increased fractional catabolic rates (P<0.01) and reduced production rates of both HDLc and ApoAI (P<0.05) compared with controls. In human ApoAI transgenic mice, levels and production rates of HDLc and human ApoAI were strikingly higher than in wild-type mice. Myriocin, an inhibitor of sphingolipid synthesis, significantly increased both HDL flux and macrophage-to-feces reverse cholesterol transport, indicating compatibility of this HDL turnover method with the macrophage-specific reverse cholesterol transport assay.
CONCLUSIONS—H2O-labeling can be used to measure HDLc and ApoAI flux in vivo, and to assess the role of genetic and pharmacological interventions on HDL turnover in mice. Safety, simplicity, and low cost of the H2O-based HDL turnover approach suggest that this assay can be scaled for human use to study effects of HDL targeted therapies on dynamic HDL function.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>23766259</pmid><doi>10.1161/ATVBAHA.113.301700</doi><tpages>10</tpages></addata></record> |
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| ispartof | Arteriosclerosis, thrombosis, and vascular biology, 2013-08, Vol.33 (8), p.1994-2003 |
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| subjects | Animals Apolipoprotein A-I - metabolism Apolipoproteins E - genetics Atherosclerosis - metabolism Cholesterol - metabolism Deuterium - pharmacokinetics Drinking - physiology Fatty Acids, Monounsaturated - pharmacology Female Humans Immunosuppressive Agents - pharmacology Lipoproteins, HDL - metabolism Liver - metabolism Macrophages - metabolism Male Mass Spectrometry - methods Mass Spectrometry - standards Mice Mice, Transgenic Water - metabolism |
| title | 2H2O-Based High-Density Lipoprotein Turnover Method for the Assessment of Dynamic High-Density Lipoprotein Function in Mice |
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