{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:06:44Z","timestamp":1791421604817,"version":"4.3.3"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001665","name":"French national research","doi-asserted-by":"publisher","award":["ANR-16-RHUS-0007"],"award-info":[{"award-number":["ANR-16-RHUS-0007"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"French national research","doi-asserted-by":"publisher","award":["ANR-R23121NN\/RPV23156NNA"],"award-info":[{"award-number":["ANR-R23121NN\/RPV23156NNA"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CHolesterol Personalized INnovation"},{"name":"INSTINCTIVE research program"},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["EQU201903007846"],"award-info":[{"award-number":["EQU201903007846"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HEPALIPA"},{"DOI":"10.13039\/501100004543","name":"Chinese Scholarship Council","doi-asserted-by":"crossref","award":["202006850007"],"award-info":[{"award-number":["202006850007"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Netherlands Cardiovascular Research Initiative"},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["CVON-GENIUS-2"],"award-info":[{"award-number":["CVON-GENIUS-2"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2009T038"],"award-info":[{"award-number":["2009T038"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the gain-of-function variant HL-E97G, with selectively increased phospholipase activity, as a new genetic cause of familial combined hypocholesterolaemia in humans. The role of HL in the development of atherosclerosis remains controversial. In this context, the action of HL-E97G on the development of atherosclerosis remains unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>To evaluate the lipid-lowering and anti-atherogenic properties of HL-E97G vs. wildtype HL (HL-WT) in hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and to assess dependence of these effects on the LDL receptor (LDLR) pathway in LDLR-deficient (Ldlr\u2212\/\u2212) mice. APOE*3.Leiden.CETP mice or Ldlr\u2212\/\u2212 mice received an intravenous injection of AAV8 expressing either eGFP (control), HL-WT or HL-E97G (3 \u00d7 1011 GC\/mouse) while being fed pro-atherogenic diets. Plasma cholesterol levels were measured monthly, and aortic atherosclerotic lesion sizes were assessed at termination. HL-E97G largely decreased plasma total cholesterol exposure in APOE*3-Leiden.CETP mice (\u221263% vs. control; \u221258% vs. HL-WT), resulting at least in part from increased uptake of (V)LDL by the liver, accompanied by a marked decrease in atherosclerotic lesion size (\u221298% vs. control; \u221297% vs. HL-WT) in the aortic root. Importantly, HL-E97G also strongly reduced plasma cholesterol exposure in Ldlr\u2212\/\u2212 mice (\u221280% vs. control; \u221277% vs. HL-WT), and decreased atherosclerotic lesion size in the aortic root (\u221254% vs. control; \u221241% vs. HL-WT) and the aortic arch (\u221273% vs. control; \u221270% vs. HL-WT).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>HL-E97G strongly reduces plasma cholesterol levels, by increasing the uptake of (V)LDL, to decrease atherosclerosis development in mice independently of the LDLR pathway. These data suggest that modulating HL function is a promising tool in patients with familial hypercholesterolaemia.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf097","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T18:13:29Z","timestamp":1748974409000},"page":"1024-1035","source":"Crossref","is-referenced-by-count":6,"title":["A rare gain of function variant of hepatic lipase attenuates hypercholesterolaemia and atherosclerosis in mice via an LDL receptor-independent mechanism"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2375-007X","authenticated-orcid":false,"given":"Thibaud","family":"Sotin","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0815-1076","authenticated-orcid":false,"given":"Xiaoke","family":"Ge","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2030-6958","authenticated-orcid":false,"given":"Milena","family":"Sch\u00f6nke","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Vince","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Thouzeau","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6447-6794","authenticated-orcid":false,"given":"Samuel","family":"Frey","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Lorant","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Krul","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda C M","family":"Pronk","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reshma","family":"Lalai","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trea C M","family":"Streefland","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwa","family":"Afkir","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-7751","authenticated-orcid":false,"given":"Wieneke","family":"Dijk","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]},{"name":"INRAE, UR BIA , Nantes F-44316 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarra","family":"Smati","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5999-2513","authenticated-orcid":false,"given":"Marieke","family":"Heijink","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niek","family":"Blomberg","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1684-1894","authenticated-orcid":false,"given":"Martin","family":"Giera","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-5908","authenticated-orcid":false,"given":"Mathilde","family":"Di Filippo","sequence":"additional","affiliation":[{"name":"26900 Service de Biochimie et Biologie mol\u00e9culaire, Laboratoire de Biologie M\u00e9dicale Multi-sites, Hospices Civils de Lyon , Lyon Cedex ,","place":["France"]},{"name":"CarMen Laboratory, INSERM, INRA, INSA Lyon, Universit\u00e9 Claude Bernard Lyon 1 , Pierre-B\u00e9nite ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9585-0571","authenticated-orcid":false,"given":"Philippe","family":"Moulin","sequence":"additional","affiliation":[{"name":"CarMen Laboratory, INSERM, INRA, INSA Lyon, Universit\u00e9 Claude Bernard Lyon 1 , Pierre-B\u00e9nite ,","place":["France"]},{"name":"26900 F\u00e9d\u00e9ration d'endocrinologie, maladies m\u00e9taboliques, diab\u00e8te et nutrition, GHE, Hospices Civils de Lyon , Bron Cedex ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0014-5571","authenticated-orcid":false,"given":"Sander","family":"Kooijman","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. Box 9600, Leiden 2300 RC ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1580-8040","authenticated-orcid":false,"given":"Bertrand","family":"Cariou","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 quai Moncousu, BP70721, Nantes F-44000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-4988","authenticated-orcid":false,"given":"Patrick C N","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department Medicine, Div. Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , P.O. 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