Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia
Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemia and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidentified “major” genes that would increase VLDL production and of “modifier” ge...
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| Format: | Article |
| Language: | English |
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Elsevier
2000-08-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520334416 |
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| author | Joan Carles Escolà-Gil Josep Julve Àfrica Marzal-Casacuberta Jordi Ordóñez-Llanos Francesc González-Sastre Francisco Blanco-Vaca |
| author_facet | Joan Carles Escolà-Gil Josep Julve Àfrica Marzal-Casacuberta Jordi Ordóñez-Llanos Francesc González-Sastre Francisco Blanco-Vaca |
| author_sort | Joan Carles Escolà-Gil |
| collection | DOAJ |
| description | Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemia and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidentified “major” genes that would increase VLDL production and of “modifier” genes that would influence the phenotype of the disease has been proposed. Expression of apolipoprotein A-II (apoA-II), a high density lipoprotein (HDL) of unknown function, in transgenic mice produced increased concentration of apoB-containing lipoproteins and decreased HDL. Here we show that expression of human apoA-II in apoE-deficient mice induces a dose-dependent increase in VLDL, resulting in plasma triglyceride elevations of up to 24-fold in a mouse line that has 2-fold the concentration of human apoA-II of normolipidemic humans, as well as other well-known characteristics of FCHL: increased concentrations of cholesterol, triglyceride, and apoB in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), reduced HDL cholesterol, normal lipoprotein lipase and hepatic lipase activities, increased production of VLDL triglycerides, and increased susceptibility to atherosclerosis. However, FCHL patients do not have plasma concentrations of human apoA-II as high as those of apoE-deficient mice overexpressing human apoA-II, and the apoA-II gene has not been linked to FCHL in genome-wide scans. Therefore, the apoA-II gene could be a “modifier” FCHL gene influencing the phenotype of the disease in some individuals through unkown mechanisms including an action on a “major” FCHL gene. We conclude that apoE-deficient mice overexpressing human apoA-II constitute useful animal models with which to study the mechanisms leading to overproduction of VLDL, and that apoA-II may function to regulate VLDL production. —Escolà-Gil, J. C., J. Julve, À. Marzal-Casacuberta, J. Ordóñez-Llanos, F. González-Sastre, and F. Blanco-Vaca. Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. J. Lipid Res. 2000. 41: 1328–1338. |
| first_indexed | 2024-12-16T13:07:28Z |
| format | Article |
| id | doaj.art-fe8e436def6c49e5992ec893144c225c |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-16T13:07:28Z |
| publishDate | 2000-08-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj.art-fe8e436def6c49e5992ec893144c225c2022-12-21T22:30:42ZengElsevierJournal of Lipid Research0022-22752000-08-0141813281338Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemiaJoan Carles Escolà-Gil0Josep Julve1Àfrica Marzal-Casacuberta2Jordi Ordóñez-Llanos3Francesc González-Sastre4Francisco Blanco-Vaca5Servei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, SpainServei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, SpainServei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, SpainServei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Barcelona, SpainServei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Barcelona, SpainServei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; To whom correspondence should be addressed.Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemia and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidentified “major” genes that would increase VLDL production and of “modifier” genes that would influence the phenotype of the disease has been proposed. Expression of apolipoprotein A-II (apoA-II), a high density lipoprotein (HDL) of unknown function, in transgenic mice produced increased concentration of apoB-containing lipoproteins and decreased HDL. Here we show that expression of human apoA-II in apoE-deficient mice induces a dose-dependent increase in VLDL, resulting in plasma triglyceride elevations of up to 24-fold in a mouse line that has 2-fold the concentration of human apoA-II of normolipidemic humans, as well as other well-known characteristics of FCHL: increased concentrations of cholesterol, triglyceride, and apoB in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), reduced HDL cholesterol, normal lipoprotein lipase and hepatic lipase activities, increased production of VLDL triglycerides, and increased susceptibility to atherosclerosis. However, FCHL patients do not have plasma concentrations of human apoA-II as high as those of apoE-deficient mice overexpressing human apoA-II, and the apoA-II gene has not been linked to FCHL in genome-wide scans. Therefore, the apoA-II gene could be a “modifier” FCHL gene influencing the phenotype of the disease in some individuals through unkown mechanisms including an action on a “major” FCHL gene. We conclude that apoE-deficient mice overexpressing human apoA-II constitute useful animal models with which to study the mechanisms leading to overproduction of VLDL, and that apoA-II may function to regulate VLDL production. —Escolà-Gil, J. C., J. Julve, À. Marzal-Casacuberta, J. Ordóñez-Llanos, F. González-Sastre, and F. Blanco-Vaca. Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. J. Lipid Res. 2000. 41: 1328–1338.http://www.sciencedirect.com/science/article/pii/S0022227520334416apoBatherosclerosishigh density lipoproteintransgenic micevery low density lipoprotein |
| spellingShingle | Joan Carles Escolà-Gil Josep Julve Àfrica Marzal-Casacuberta Jordi Ordóñez-Llanos Francesc González-Sastre Francisco Blanco-Vaca Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia Journal of Lipid Research apoB atherosclerosis high density lipoprotein transgenic mice very low density lipoprotein |
| title | Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia |
| title_full | Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia |
| title_fullStr | Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia |
| title_full_unstemmed | Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia |
| title_short | Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia |
| title_sort | expression of human apolipoprotein a ii in apolipoprotein e deficient mice induces features of familial combined hyperlipidemia |
| topic | apoB atherosclerosis high density lipoprotein transgenic mice very low density lipoprotein |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520334416 |
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