Abstract
Background and aimsApolipoprotein (apo) C1 is a 6.6 kDa protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance, and it also favors cholesterol accumulation in HDL, especially by inhibiting CETP in human plasma. Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models expressing CETP, like in humans, is not known. This study aimed at determining the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but with endogenous apoC1 without CETP inhibitory potential. MethodsRabbits expressing a human apoC1 transgene (HuApoC1Tg) were generated and displayed significant amounts of human apoC1 in plasma. ResultsAfter cholesterol feeding, atherosclerosis lesions were significantly less extensive (−22%, p < 0.05) and HDL displayed a reduced ability to serve as CETP substrates (−25%, p < 0.05) in HuApoC1Tg rabbits than in WT littermates. It was associated with rises in plasma HDL cholesterol level and PON-1 activity, and a decrease in the plasma level of the lipid oxidation markers 12(S)-HODE and 8(S)HETE. In chow-fed animals, the level of HDL-cholesterol was also significantly higher in HuApoC1Tg than in WT animals (0.83 ± 0.11 versus 0.73 ± 0.11 mmol/L, respectively, p < 0.05), and it was associated with significantly lower CETP activity (cholesteryl ester transfer rate, −10%, p < 0.05; specific CETP activity, −14%, p < 0.05). ConclusionsConstitutive expression of fully functional human apoC1 in transgenic rabbit attenuates atherosclerosis. It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL.
Highlights
Human apolipoprotein C1 is the smallest plasma apolipopro tein, with 57 amino-acid residues and a molecular weight of 6.6 kDa [1]
The present study reports the generation of a new line of transgenic rabbits expressing human apoC1
Despite the ubiquitous expression pattern of the transgene, which significantly differs from what is observed in mice and primates [27], human apoC1 was a secreted protein mainly associated with circulating lipoproteins
Summary
Human apolipoprotein (apo) C1 is the smallest plasma apolipopro tein, with 57 amino-acid residues and a molecular weight of 6.6 kDa [1]. Results: After cholesterol feeding, atherosclerosis lesions were significantly less extensive (− 22%, p < 0.05) and HDL displayed a reduced ability to serve as CETP substrates (− 25%, p < 0.05) in HuApoC1Tg rabbits than in WT littermates. It was associated with rises in plasma HDL cholesterol level and PON-1 activity, and a decrease in the plasma level of the lipid oxidation markers 12(S)-HODE and 8(S)HETE. It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL
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