title: Human ApoA-II inhibits the hydrolysis of HDL triglyceride and the decrease of HDL size induced by hypertriglyceridemia and cholesteryl ester transfer protein in transgenic mice.
abstract: The plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters with triglycerides of other lipoproteins. Subsequent lipolysis of the triglyceride-enriched HDL by hepatic lipase leads to reductions of HDL size and apoA-I content. To investigate a possible modulation of the effects of CETP by apoA-II, human CETP transgenic mice were cross-bred with transgenic mice expressing human apoA-II and, in some cases, human apoA-I and apoC-III (with human-like HDL and hypertriglyceridemia). CETP expression resulted in reductions of HDL and increases in VLDL cholesteryl ester in mice expressing human apoA-II, alone or in combination with apoA-I and apoC-III, indicating that apoA-II does not inhibit the cholesteryl ester transfer activity of CETP. However, CETP expression resulted in more prominent increases in HDL triglyceride in mice expressing both apoA-II and CETP, especially in CETP/apoA-II/apoAI-CIII transgenic mice. CETP expression caused dramatic reductions in HDL size and apoA-I content in apoAI-CIII transgenic mice, but not in apoA-II/AI-CIII transgenic mice. HDL prepared from mice of various genotypes showed inhibition of emulsion-based hepatic lipase activity in proportion to the apoA-II/apoA-I ratio of HDL. The presence of human apoA-II also inhibited mouse plasma hepatic lipase activity on HDL triglyceride. Thus, apoA-II does not inhibit the lipid transfer activity of CETP in vivo. However, coexpression of apoA-II with CETP results in HDL particles that are more triglyceride enriched and resistant to reductions in size and apoA-I content, reflecting inhibition of hepatic lipase by apoA-II. The inhibition of HDL remodeling by apoA-II could explain the relatively constant levels of HDL containing both apoA-I and apoA-II in human populations.
authors.affiliation: Department of Medicine, Columbia University, New York 10032.
authors.forename: S
authors.initials: S
authors.lastname: Zhong
authors.forename: I J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: C
authors.initials: C
authors.lastname: Bruce
authors.forename: E
authors.initials: E
authors.lastname: Rubin
authors.forename: J L
authors.initials: JL
authors.lastname: Breslow
authors.forename: A
authors.initials: A
authors.lastname: Tall
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000235:genetics / Q000378:metabolism*; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D006801:Humans; D015228:Hypertriglyceridemia / Q000378:metabolism*; D008049:Lipase / Q000032:analysis; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010316:Particle Size; D013045:Species Specificity; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D008049:Lipase