Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1

Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1

Jong, M.C.
Dahlmans, V.E.H.
van Gorp, P.J.J.
Breuer, M.L.
Mol, M.J.T.M.
van der Zee, A.
Frants, R.R.
Hofker, M.H.
Havekes, L.M.
Gaubius Instituut TNO

1996

Transgenic mice overexpressing human APOE*3Leiden are highly susceptible to diet-induced hyperlipoproteinemia and atherosclerosis due to a defect in hepatic uptake of remnant lipoproteins. In addition to the human APOE*3Leiden gene, these mice carry the human APOC1 gene (APOE*3Leiden- C1). To investigate the possible effect of simultaneous expression of the human APOC1 gene, we examined the phenotypic expression in these APOE*3Leiden-C1 mice in relation to transgenic mice expressing the APOE*3Leiden gene without the APOC1 gene (APOE*3Leiden-HCR), APOE*3Leiden-C1 and APOE*3Leiden-HCR mice had comparable liver expression for the APOE*3Leiden transgene and high total cholesterol levels on a sucrose-based diet compared with control mice (4.3 and 4.3 versus 2.1 mmol/L). In addition, on this diet APOE*3Leiden-C1 mice displayed significantly higher serum triglyceride levels than APOE*3Leiden-HCR mice and control mice (4.4 versus 0.6 and 0.2 mmol/L). Elevated triglyceride and cholesterol levels were mainly in the VLDL-sized lipoproteins. In vivo turnover studies with endogenously triglyceride-labeled VLDL showed a reduced VLDL triglyceride fractional catabolic rate for APOE*3Leiden-C1 and APOE*3Leiden-HCR mice compared with control mice (3.5 and 11.0 versus 20.4 pools per hour). To study whether the difference in fractional catabolic rates between the two transgenic strains was due to an inhibiting effect of apoC1 on the extrahepatic lipolysis or hepatic-mediated uptake of VLDL, turnover experiments were performed in functionally hepatectomized mice. Strikingly, both APOE*3Leiden-C1 and APOE*3Leiden-HCR mice showed a decreased lipolytic rate of VLDL triglyceride in the extrahepatic circulation compared with control mice (1.5 and 1.8 versus 6.3 pools per hour). We conclude that next to an impaired hepatic uptake, overexpression of the APOE*3Leiden gene influences the extrahepatic lipolysis of VLDL triglycerides, whereas simultaneous overexpression of the APOC1 gene leads to a further decrease in hepatic clearance of VLDL. Chemicals/CAS: Apolipoprotein C-I; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins C; Apolipoproteins E; Cholesterol, 57-88-5; Cholesterol, Dietary; Lipoproteins, VLDL; Triglycerides

Health
Transgenic mice
Triacylglycerol
Very low density lipoprotein
Animal experiment
Animal model
Atherosclerosis
Cholesterol blood level
Controlled study
Female
Lipolysis
Liver clearance
Liver metabolism
Male
Nonhuman
Protein transport
Transgenic mouse
Triacylglycerol blood level
Animals
Apolipoprotein C-I
Apolipoprotein E3
Apolipoproteins C
Apolipoproteins E
Arteriosclerosis
Cholesterol
Cholesterol, Dietary
Gene Expression
Humans
Hyperlipoproteinemias
Lipolysis
Lipoproteins, VLDL
Liver
Mice
Mice, Transgenic
Triglycerides

http://resolver.tudelft.nl/uuid:f521091b-8bbf-4c33-9e54-b86ed7687d3d

233431

1079-5642

Arteriosclerosis, Thrombosis, and Vascular Biology, 16 (8), 934-940

article