Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen
Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissu...
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| Veröffentlicht in: | The Journal of clinical investigation 2023-12, Vol.133 (23), p.1-15 |
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| creator | Yang, Ye Beigneux, Anne P Song, Wenxin Nguyen, Le Phuong Jung, Hyesoo Tu, Yiping Weston, Thomas A Tran, Caitlyn M Xie, Katherine Yu, Rachel G Tran, Anh P Miyashita, Kazuya Nakajima, Katsuyuki Murakami, Masami Chen, Yan Q Zhen, Eugene Y Kim, Joonyoung R Kim, Paul H Birrane, Gabriel Tontonoz, Peter Ploug, Michael Konrad, Robert J Fong, Loren G Young, Stephen G |
| description | Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism. |
| doi_str_mv | 10.1172/JCI172600 |
| format | Article |
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By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI172600</identifier><identifier>PMID: 37824203</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adipose tissue (brown) ; Animals ; Apolipoprotein A-V - genetics ; Apolipoproteins ; Biomedical research ; Blood vessels ; Body fat ; Capillaries ; Capillaries - metabolism ; Cardiovascular disease ; Heart ; Heparan sulfate ; Heparan sulfate proteoglycans ; Hypertriglyceridemia ; Hypertriglyceridemia - genetics ; Hypertriglyceridemia - metabolism ; Hypotheses ; Immunohistochemistry ; Lipase ; Lipoprotein lipase ; Lipoprotein Lipase - genetics ; Lipoprotein Lipase - metabolism ; Lipoproteins ; Metabolism ; Mice ; Molecular modelling ; Mutation ; Plasma ; Ratios ; Receptors, Lipoprotein - genetics ; Receptors, Lipoprotein - metabolism ; Triglycerides - blood</subject><ispartof>The Journal of clinical investigation, 2023-12, Vol.133 (23), p.1-15</ispartof><rights>Copyright American Society for Clinical Investigation Dec 2023</rights><rights>2023 Yang et al. 2023 Yang et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-c75a4021825c004f7914583e8daf8be0e6459d68a9e46a413bc5eb79a75b52ad3</citedby><cites>FETCH-LOGICAL-c404t-c75a4021825c004f7914583e8daf8be0e6459d68a9e46a413bc5eb79a75b52ad3</cites><orcidid>0000-0001-9311-6077 ; 0000-0002-0162-5665 ; 0000-0001-7270-3176 ; 0000-0002-6343-4338 ; 0000-0002-4465-5290 ; 0000-0002-6568-4461 ; 0000-0003-3720-8633 ; 0000-0003-2215-4265 ; 0000-0002-1798-8938 ; 0000-0003-1259-0477 ; 0000-0003-4260-7700 ; 0000-0002-7892-150X ; 0000-0002-4630-9113 ; 0000-0001-8795-5712 ; 0000-0002-8429-651X ; 0000-0002-3783-1452</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688983/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688983/$$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/37824203$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Ye</creatorcontrib><creatorcontrib>Beigneux, Anne P</creatorcontrib><creatorcontrib>Song, Wenxin</creatorcontrib><creatorcontrib>Nguyen, Le Phuong</creatorcontrib><creatorcontrib>Jung, Hyesoo</creatorcontrib><creatorcontrib>Tu, Yiping</creatorcontrib><creatorcontrib>Weston, Thomas A</creatorcontrib><creatorcontrib>Tran, Caitlyn M</creatorcontrib><creatorcontrib>Xie, Katherine</creatorcontrib><creatorcontrib>Yu, Rachel G</creatorcontrib><creatorcontrib>Tran, Anh P</creatorcontrib><creatorcontrib>Miyashita, Kazuya</creatorcontrib><creatorcontrib>Nakajima, Katsuyuki</creatorcontrib><creatorcontrib>Murakami, Masami</creatorcontrib><creatorcontrib>Chen, Yan Q</creatorcontrib><creatorcontrib>Zhen, Eugene Y</creatorcontrib><creatorcontrib>Kim, Joonyoung R</creatorcontrib><creatorcontrib>Kim, Paul H</creatorcontrib><creatorcontrib>Birrane, Gabriel</creatorcontrib><creatorcontrib>Tontonoz, Peter</creatorcontrib><creatorcontrib>Ploug, Michael</creatorcontrib><creatorcontrib>Konrad, Robert J</creatorcontrib><creatorcontrib>Fong, Loren G</creatorcontrib><creatorcontrib>Young, Stephen G</creatorcontrib><title>Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.</description><subject>Adipose tissue (brown)</subject><subject>Animals</subject><subject>Apolipoprotein A-V - genetics</subject><subject>Apolipoproteins</subject><subject>Biomedical research</subject><subject>Blood vessels</subject><subject>Body fat</subject><subject>Capillaries</subject><subject>Capillaries - metabolism</subject><subject>Cardiovascular disease</subject><subject>Heart</subject><subject>Heparan sulfate</subject><subject>Heparan sulfate proteoglycans</subject><subject>Hypertriglyceridemia</subject><subject>Hypertriglyceridemia - genetics</subject><subject>Hypertriglyceridemia - metabolism</subject><subject>Hypotheses</subject><subject>Immunohistochemistry</subject><subject>Lipase</subject><subject>Lipoprotein lipase</subject><subject>Lipoprotein Lipase - genetics</subject><subject>Lipoprotein Lipase - metabolism</subject><subject>Lipoproteins</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>Mutation</subject><subject>Plasma</subject><subject>Ratios</subject><subject>Receptors, Lipoprotein - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Ye</au><au>Beigneux, Anne P</au><au>Song, Wenxin</au><au>Nguyen, Le Phuong</au><au>Jung, Hyesoo</au><au>Tu, Yiping</au><au>Weston, Thomas A</au><au>Tran, Caitlyn M</au><au>Xie, Katherine</au><au>Yu, Rachel G</au><au>Tran, Anh P</au><au>Miyashita, Kazuya</au><au>Nakajima, Katsuyuki</au><au>Murakami, Masami</au><au>Chen, Yan Q</au><au>Zhen, Eugene Y</au><au>Kim, Joonyoung R</au><au>Kim, Paul H</au><au>Birrane, Gabriel</au><au>Tontonoz, Peter</au><au>Ploug, Michael</au><au>Konrad, Robert J</au><au>Fong, Loren G</au><au>Young, Stephen G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2023-12-01</date><risdate>2023</risdate><volume>133</volume><issue>23</issue><spage>1</spage><epage>15</epage><pages>1-15</pages><issn>1558-8238</issn><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>37824203</pmid><doi>10.1172/JCI172600</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-9311-6077</orcidid><orcidid>https://orcid.org/0000-0002-0162-5665</orcidid><orcidid>https://orcid.org/0000-0001-7270-3176</orcidid><orcidid>https://orcid.org/0000-0002-6343-4338</orcidid><orcidid>https://orcid.org/0000-0002-4465-5290</orcidid><orcidid>https://orcid.org/0000-0002-6568-4461</orcidid><orcidid>https://orcid.org/0000-0003-3720-8633</orcidid><orcidid>https://orcid.org/0000-0003-2215-4265</orcidid><orcidid>https://orcid.org/0000-0002-1798-8938</orcidid><orcidid>https://orcid.org/0000-0003-1259-0477</orcidid><orcidid>https://orcid.org/0000-0003-4260-7700</orcidid><orcidid>https://orcid.org/0000-0002-7892-150X</orcidid><orcidid>https://orcid.org/0000-0002-4630-9113</orcidid><orcidid>https://orcid.org/0000-0001-8795-5712</orcidid><orcidid>https://orcid.org/0000-0002-8429-651X</orcidid><orcidid>https://orcid.org/0000-0002-3783-1452</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1558-8238 |
| ispartof | The Journal of clinical investigation, 2023-12, Vol.133 (23), p.1-15 |
| issn | 1558-8238 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10688983 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adipose tissue (brown) Animals Apolipoprotein A-V - genetics Apolipoproteins Biomedical research Blood vessels Body fat Capillaries Capillaries - metabolism Cardiovascular disease Heart Heparan sulfate Heparan sulfate proteoglycans Hypertriglyceridemia Hypertriglyceridemia - genetics Hypertriglyceridemia - metabolism Hypotheses Immunohistochemistry Lipase Lipoprotein lipase Lipoprotein Lipase - genetics Lipoprotein Lipase - metabolism Lipoproteins Metabolism Mice Molecular modelling Mutation Plasma Ratios Receptors, Lipoprotein - genetics Receptors, Lipoprotein - metabolism Triglycerides - blood |
| title | Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen |
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