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Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia.
J Lipid Res. 2000 Aug; 41(8):1328-38.JL

Abstract

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.

Authors+Show Affiliations

Servei de Bioquímica de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10946021

Citation

Escolà-Gil, J C., et al. "Expression of Human Apolipoprotein A-II in Apolipoprotein E-deficient Mice Induces Features of Familial Combined Hyperlipidemia." Journal of Lipid Research, vol. 41, no. 8, 2000, pp. 1328-38.
Escolà-Gil JC, Julve J, Marzal-Casacuberta A, et al. Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. J Lipid Res. 2000;41(8):1328-38.
Escolà-Gil, J. C., Julve, J., Marzal-Casacuberta, A., Ordóñez-Llanos, J., González-Sastre, F., & Blanco-Vaca, F. (2000). Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. Journal of Lipid Research, 41(8), 1328-38.
Escolà-Gil JC, et al. Expression of Human Apolipoprotein A-II in Apolipoprotein E-deficient Mice Induces Features of Familial Combined Hyperlipidemia. J Lipid Res. 2000;41(8):1328-38. PubMed PMID: 10946021.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. AU - Escolà-Gil,J C, AU - Julve,J, AU - Marzal-Casacuberta,A, AU - Ordóñez-Llanos,J, AU - González-Sastre,F, AU - Blanco-Vaca,F, PY - 2000/8/18/pubmed PY - 2000/10/14/medline PY - 2000/8/18/entrez SP - 1328 EP - 38 JF - Journal of lipid research JO - J. Lipid Res. VL - 41 IS - 8 N2 - 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. SN - 0022-2275 UR - https://www.unboundmedicine.com/medline/citation/10946021/Expression_of_human_apolipoprotein_A_II_in_apolipoprotein_E_deficient_mice_induces_features_of_familial_combined_hyperlipidemia_ L2 - http://www.jlr.org/cgi/pmidlookup?view=long&pmid=10946021 DB - PRIME DP - Unbound Medicine ER -